CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-β signaling Oncogene (IF 6.854) Pub Date : 2018-11-15 Zhiqiang Zhao, Dapeng Hao, Li Wang, Jingjing Li, Yuan Meng, Peipei Li, Yuan Wang, Chao Zhang, Haisheng Zhou, Kevin Gardner, Li-jun Di
Metastasis is the process through which the primary cancer cells spread beyond the primary tumor and disseminate to other organs. Most cancer patients die of metastatic disease. EMT is proposed to be the initial event associated with cancer metastasis and how it occurred is still a mystery. CtBP is known as a co-repressor abundantly expressed in many types of cancer and regulates genes involved in cancer initiation, progression, and metastasis. We found that CtBP regulates intracellular cholesterol homeostasis in breast cancer cells by forming a complex with ZEB1 and transcriptionally repressing SREBF2 expression. Importantly, CtBP repression of intracellular cholesterol abundance leads to increased EMT and cell migration. The reason is that cholesterol negatively regulates the stability of TGF-β receptors on the cell membrane. Interestingly, TGF-β is also capable of reducing intracellular cholesterol relying on the increased recruitment of ZEB1 and CtBP complex to SREBF2 promoter. Thus, we propose a feedback loop formed by CtBP, cholesterol, and TGF-β signaling pathway, through which TGF-β triggers the cascade that mobilizes the cancer cells for metastasis. Consistently, the intravenous injection of breast cancer cells with ectopically CtBP expression show increased lung metastasis depending on the reduction of intracellular cholesterol. Finally, we analyzed the public breast cancer datasets and found that CtBP expression negatively correlates with SREBF2 and HMGCR expressions. High expression of CtBP and low expression of SREBF2 and HMGCR significantly correlates with high EMT of the primary tumors.
Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer Oncogene (IF 6.854) Pub Date : 2018-11-15 Sushil Kumar, Ratnesh Kumar Srivastav, David W. Wilkes, Taylor Ross, Sabrina Kim, Jules Kowalski, Srinivas Chatla, Qing Zhang, Anupma Nayak, Manti Guha, Serge Y. Fuchs, Christoforos Thomas, Rumela Chakrabarti
Aberrant Notch signaling is implicated in several cancers, including breast cancer. However, the mechanistic details of the specific receptors and function of ligand-mediated Notch signaling that promote breast cancer remains elusive. In our studies we show that DLL1, a Notch signaling ligand, is significantly overexpressed in ERα+ luminal breast cancer. Intriguingly, DLL1 overexpression correlates with poor prognosis in ERα+ luminal breast cancer, but not in other subtypes of breast cancer. In addition, this effect is specific to DLL1, as other Notch ligands (DLL3, JAGGED1, and JAGGED2) do not influence the clinical outcome of ERα+ patients. Genetic studies show that DLL1-mediated Notch signaling in breast cancer is important for tumor cell proliferation, angiogenesis, and cancer stem cell function. Consistent with prognostic clinical data, we found the tumor-promoting function of DLL1 is exclusive to ERα+ luminal breast cancer, as loss of DLL1 inhibits both tumor growth and lung metastasis of luminal breast cancer. Importantly, we find that estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysososmal degradations. Moreover, estrogen inhibits ubiquitination of DLL1. Together, our results highlight an unexpected and novel subtype-specific function of DLL1 in promoting luminal breast cancer that is regulated by estrogen signaling. Our studies also emphasize the critical role of assessing subtype-specific mechanisms driving tumor growth and metastasis to generate effective subtype-specific therapeutics.
SATB family chromatin organizers as master regulators of tumor progression Oncogene (IF 6.854) Pub Date : 2018-11-09 Rutika Naik, Sanjeev Galande
SATB (Special AT-rich binding protein) family proteins have emerged as key regulators that integrate higher-order chromatin organization with the regulation of gene expression. Studies over the past decade have elucidated the specific roles of SATB1 and SATB2, two closely related members of this family, in cancer progression. SATB family chromatin organizers play diverse and important roles in regulating the dynamic equilibrium of apoptosis, cell invasion, metastasis, proliferation, angiogenesis, and immune modulation. This review highlights cellular and molecular events governed by SATB1 influencing the structural organization of chromatin and interacting with several co-activators and co-repressors of transcription towards tumor progression. SATB1 expression across tumor cell types generates cellular and molecular heterogeneity culminating in tumor relapse and metastasis. SATB1 exhibits dynamic expression within intratumoral cell types regulated by the tumor microenvironment, which culminates towards tumor progression. Recent studies suggested that cell-specific expression of SATB1 across tumor recruited dendritic cells (DC), cytotoxic T lymphocytes (CTL), T regulatory cells (Tregs) and tumor epithelial cells along with tumor microenvironment act as primary determinants of tumor progression and tumor inflammation. In contrast, SATB2 is differentially expressed in an array of cancer types and is involved in tumorigenesis. Survival analysis for patients across an array of cancer types correlated with expression of SATB family chromatin organizers suggested tissue-specific expression of SATB1 and SATB2 contributing to disease prognosis. In this context, it is pertinent to understand molecular players, cellular pathways, genetic and epigenetic mechanisms governed by cell types within tumors regulated by SATB proteins. We propose that patient survival analysis based on the expression profile of SATB chromatin organizers would facilitate their unequivocal establishment as prognostic markers and therapeutic targets for cancer therapy.
ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma Oncogene (IF 6.854) Pub Date : 2018-11-06 Laura Asnaghi, David T. White, Nolan Key, Joshua Choi, Alka Mahale, Hind Alkatan, Deepak P. Edward, Sahar M. Elkhamary, Saleh Al-Mesfer, Azza Maktabi, Christopher G. Hurtado, Grace Y. Lee, Angel M. Carcaboso, Jeff S. Mumm, Leen Abu Safieh, Charles G. Eberhart
Retinoblastoma is the most common intraocular cancer in children. While the primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination is generally resistant to therapy and remains a leading cause of pediatric cancer death in much of the world. In order to identify new therapeutic targets in aggressive tumors, we sequenced RNA transcripts in five snap frozen retinoblastomas which invaded the optic nerve and five which did not. A three-fold increase was noted in mRNA levels of ACVR1C/ALK7, a type I receptor of the TGF-β family, in invasive retinoblastomas, while downregulation of DACT2 and LEFTY2, negative modulators of the ACVR1C signaling, was observed in most invasive tumors. A two- to three-fold increase in ACVR1C mRNA was also found in invasive WERI Rb1 and Y79 cells as compared to non-invasive cells in vitro. Transcripts of ACVR1C receptor and its ligands (Nodal, Activin A/B, and GDF3) were expressed in six retinoblastoma lines, and evidence of downstream SMAD2 signaling was present in all these lines. Pharmacological inhibition of ACVR1C signaling using SB505124, or genetic downregulation of the receptor using shRNA potently suppressed invasion, growth, survival, and reduced the protein levels of the mesenchymal markers ZEB1 and Snail. The inhibitory effects on invasion, growth, and proliferation were recapitulated by knocking down SMAD2, but not SMAD3. Finally, in an orthotopic zebrafish model of retinoblastoma, a 55% decrease in tumor spread was noted (p = 0.0026) when larvae were treated with 3 µM of SB505124, as compared to DMSO. Similarly, knockdown of ACVR1C in injected tumor cells using shRNA also resulted in a 54% reduction in tumor dissemination in the zebrafish eye as compared to scrambled shRNA control (p = 0.0005). Our data support a role for the ACVR1C/SMAD2 pathway in promoting invasion and growth of retinoblastoma.
Unbalanced YAP–SOX9 circuit drives stemness and malignant progression in esophageal squamous cell carcinoma Oncogene (IF 6.854) Pub Date : 2018-11-06 Lianghai Wang, Zhiyu Zhang, Xiaodan Yu, Xuan Huang, Zheng Liu, Yuhang Chai, Lei Yang, Qian Wang, Man Li, Jin Zhao, Jun Hou, Feng Li
Yes-associated protein (YAP) has been identified as a key regulator of tissue homeostasis. However, the precise role and regulatory mechanism of YAP in esophageal squamous cell carcinoma (ESCC) remains unclear. Here we report that the genetic or pharmacological inhibition of YAP repressed cancer stem cell (CSC)-like properties, including tumorsphere-forming potential, cell motility, and chemoresistance in vitro, and was sufficient to attenuate tumor growth and CSC marker expression in ESCC xenografts. Mechanistically, YAP transcriptionally activated its downstream target SOX9 via TEAD1-mediated binding. We also observed a positive correlation between YAP signaling and SOX9 expression in two independent clinical cohorts. Intriguingly, YAP-targeting microRNAs, including miR-506-3p, which were induced by SOX9, post-transcriptionally repressed YAP expression, contributing to a negative feedback mechanism. Dual inhibition of YAP and SOX9 robustly suppressed malignant phenotypes. Notably, ESCC samples from The Cancer Genome Atlas (TCGA) dataset had frequent (44%) instances of YAP gene amplification and genetic inactivation of Hippo pathway regulators. Nuclear YAP expression was elevated in 197 ESCC tissues from a Chinese cohort. Together, our findings provide evidence that genetic hyperactivation of YAP unbalances the YAP–SOX9 feedback loop and confers CSC-like features in ESCC, suggesting that this YAP–SOX9 circuit represents a potential therapeutic target.
TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation Oncogene (IF 6.854) Pub Date : 2018-11-06 Akihiro Matsushita, Tatsuhiro Sato, Satomi Mukai, Teruaki Fujishita, Emi Mishiro-Sato, Maho Okuda, Masahiro Aoki, Yoshinori Hasegawa, Yoshitaka Sekido
Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40–50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified. Here, we show that TAZ is expressed and underphosphorylated (activated) in the majority of MM cells compared to immortalized mesothelial cells. ShRNA-mediated TAZ knockdown highly suppressed cell proliferation, anchorage-independent growth, cell motility, and invasion in MM cells harboring activated TAZ. Conversely, transduction of an activated form of TAZ in immortalized mesothelial cells enhanced these in vitro phenotypes and conferred tumorigenicity in vivo. Microarray analysis determined that activated TAZ most significantly enhanced the transcription of genes related to “cytokine-cytokine receptor interaction.” Among selected cytokines, we found that IL-1 signaling activation plays a major role in proliferation in TAZ-activated MM cells. Both IL1B knockdown and an IL-1 receptor antagonist significantly suppressed malignant phenotypes of immortalized mesothelial cells and MM cells with activated TAZ. Overall, these results indicate an oncogenic role for TAZ in MMs via transcriptional induction of distinct pro-oncogenic genes including cytokines. Among these, IL-1 signaling appears as one of the most important cascades, thus potentially serving as a target pathway in MM cells harboring Hippo pathway inactivation.
Correction: CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer Oncogene (IF 6.854) Pub Date : 2018-11-05 A. Lujambio, A. Portela, J. Liz, S. A. Melo, S. Rossi, R. Spizzo, C. M. Croce, G. A. Calin, M. Esteller
Correction: CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer Correction: CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer, Published online: 05 November 2018; doi:10.1038/s41388-018-0560-1 Correction: CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer
Correction: ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling Oncogene (IF 6.854) Pub Date : 2018-11-02 Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan, Wen-Ying Liao, Chih-Pin Chuu, Wei-Yu Chen, Chi-Rong Li, Ching-Yu Lin, Shu-Pin Huang, Li-Tzong Chen, Kelvin K. Tsai
Correction: ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling Correction: ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling, Published online: 02 November 2018; doi:10.1038/s41388-018-0561-0 Correction: ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling
p53-dependent autophagic degradation of TET2 modulates cancer therapeutic resistance Oncogene (IF 6.854) Pub Date : 2018-11-02 Jixiang Zhang, Peng Tan, Lei Guo, Jing Gong, Jingjing Ma, Jia Li, Minjung Lee, Shaohai Fang, Ji Jing, Gavin Johnson, Deqiang Sun, Wen-ming Cao, Roderick Dashwood, Leng Han, Yubin Zhou, Wei-Guo Dong, Yun Huang
Tumor cells with p53 inactivation frequently exhibit chemotherapy resistance, which poses a long-standing challenge to cancer treatment. Here we unveiled a previously unrecognized role of TET2 in mediating p53-loss induced chemotherapy resistance in colon cancer. Deletion of TET2 in p53-null colon cancer cells enhanced DNA damage and restored chemotherapy sensitivity. By taking a two-pronged approach that combined pharmacological inhibition with genetic depletion, we discovered that p53 destabilized TET2 at the protein level by promoting its autophagic degradation. At the molecular level, we further revealed a physical association between TET2 and p53 that facilitated the nucleoplasmic shuttling of TET2, as well as its recruitment to the autophagosome for degradation. Our study has unveiled a functional interplay between TET2 and p53 during anti-cancer therapy. Our findings establish the rationale for targeting TET2 to overcome chemotherapy resistance associated with mutant p53 tumors.
Tissue necrosis and its role in cancer progression Oncogene (IF 6.854) Pub Date : 2018-11-02 Adi Karsch-Bluman, Ariel Feiglin, Eliran Arbib, Tal Stern, Hila Shoval, Ouri Schwob, Michael Berger, Ofra Benny
Great efforts have been made in revealing the mechanisms governing cancer resistance and recurrence. The in-situ effects of cell death, caused by hypoxia and metabolic stress, were largely studied in association with inflammation. However, in this work, we focused on the direct effects of necrosis on cancer promotion and on the tumor microenvironment. The conditions leading to cell necrosis, upon nutrient and oxygen deprivation, were recapitulated in-vitro and were used to generate samples for computational proteomic analysis. Under these conditions, we identified clusters of enriched pathways that may be involved in tumor resistance, leading to cancer recurrence. We show that the content of necrotic cells enhances angiogenesis and proliferation of endothelial cells, induces vasculature, as well as increases migration, invasion, and cell-cell interactions. In-vivo studies, where MDA-MB-231 xenografts were exposed to necrotic lysates, resulted in an increase in both proliferation and angiogenesis. Histological analysis of tumor tissues revealed high expression levels of key mediators that were identified by proteomic analysis. Moreover, when cells were injected systemically, coupled with necrotic lysates, a higher number of large lesions was detected in the lung. Finally, using xenografts, we demonstrated that combining an antagonist of a necrotic signal with an anticancer treatment potentiates the prolonged therapeutic effect. This approach suggests a paradigm shift in which targeting late necrotic-secreted factors may increase survival and enhance the efficacy of anticancer therapy.
Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP Oncogene (IF 6.854) Pub Date : 2018-11-02 Caiyan Zhang, Huimin Wang, Xiaomin Liu, Yanping Hu, Lei Ding, Xing Zhang, Qiangling Sun, Yanli Li
Lung cancer is one of the most common malignant diseases globally, composed of non-small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). MicroRNAs (miRNAs) are single-stranded noncoding RNAs having important roles in lung cancer development. miR-411-5p/3p were reported to be increased significantly in human NSCLC tissues and cell lines. Moreover, miR-411-5p/3p overexpression could accelerate cell proliferation and migration, and impede cell apoptosis in NSCLC cell lines. Mechanically, SPRY4 is confirmed a direct target of miR-411-5p/3p. Furthermore, our findings showed that miR-411-5p/3p promoted lung tumor growth in vivo, decreased SPRY4 expression dramatically, and induced EGFR, AKT signaling activation, as well as epithelial–mesenchymal transition (EMT) simultaneously in tumor tissues. In addition, we showed that miR-411-5p also targeted tumor suppressor TXNIP, involved in regulating positively cell cycle progress in SPC-A1 cells rather than in H1299. Whether cell specificity of low TXNIP mRNA level in H1299 is responsible for the different response to cell cycle between H1299 and SPC-A1 would need further explorations. Collectively, these results suggest that miR-411-5p/3p are required for NSCLC development by suppressing SPRY4 and TXNIP; thus, the miR-411-SPRY4-AKT axis might act as a promising target for lung cancer therapy clinically.
Overexpression-mediated activation of MET in the Golgi promotes HER3/ERBB3 phosphorylation Oncogene (IF 6.854) Pub Date : 2018-11-02 Nicole Michael Frazier, Toni Brand, John D. Gordan, Jennifer Grandis, Natalia Jura
Ligand-dependent oligomerization of receptor tyrosine kinases (RTKs) results in their activation through highly specific conformational changes in the extracellular and intracellular receptor domains. These conformational changes are unique for each RTK subfamily, limiting cross-activation between unrelated RTKs. The proto-oncogene MET receptor tyrosine kinase overcomes these structural constraints and phosphorylates unrelated RTKs in numerous cancer cell lines. The molecular basis for these interactions is unknown. We investigated the mechanism by which MET phosphorylates the human epidermal growth factor receptor-3 (HER3 or ERBB3), a catalytically impaired RTK whose phosphorylation by MET has been described as an essential component of drug resistance to inhibitors targeting EGFR and HER2. We find that in untransformed cells, HER3 is not phosphorylated by MET in response to ligand stimulation, but rather to increasing levels of MET expression, which results in ligand-independent MET activation. Phosphorylation of HER3 by its canonical co-receptors, EGFR and HER2, is achieved by engaging an allosteric site on the HER3 kinase domain, but this site is not required when HER3 is phosphorylated by MET. We also observe that HER3 preferentially interacts with MET during its maturation along the secretory pathway, before MET is post translationally processed by cleavage within its extracellular domain. This results in accumulation of phosphorylated HER3 in the Golgi apparatus. We further show that in addition to HER3, MET phosphorylates other RTKs in the Golgi, suggesting that this mechanism is not limited to HER3 phosphorylation. These data demonstrate a link between MET overexpression and its aberrant activation in the Golgi endomembranes and suggest that non-canonical interactions between MET and other RTKs occur during maturation of receptors. Our study highlights a novel aspect of MET signaling in cancer that would not be accessible to inhibition by therapeutic antibodies.
Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance Oncogene (IF 6.854) Pub Date : 2018-11-02 Y.-B. Hu, C. Yan, L. Mu, Y.–L. Mi, H. Zhao, H. Hu, X.-L. Li, D.-D. Tao, Y.-Q. Wu, J.-P. Gong, J.-C. Qin
Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Bioinformatics-based analysis reveals elevated MFSD12 as a key promoter of cell proliferation and a potential therapeutic target in melanoma Oncogene (IF 6.854) Pub Date : 2018-11-01 Chuan-Yuan Wei, Meng-Xuan Zhu, Nan-Hang Lu, Rui Peng, Xuan Yang, Peng-Fei Zhang, Lu Wang, Jian-Ying Gu
Although recent therapeutic advances based on our understanding of molecular phenomena have prolonged the survival of melanoma patients, the prognosis of melanoma remains dismal and further understanding of the underlying mechanism of melanoma progression is needed. In this study, differential expression analyses revealed that many genes, including AKT1 and CDK2, play important roles in melanoma. Functional analyses of differentially expressed genes (DEGs), obtained from the GEO (Gene Expression Omnibus) database, indicated that high proliferative and metastatic abilities are the main characteristics of melanoma and that the PI3K and MAPK pathways play essential roles in melanoma progression. Among these DEGs, major facilitator superfamily domain-containing 12 (MFSD12) was found to have significantly and specifically upregulated expression in melanoma, and elevated MFSD12 level promoted cell proliferation by promoting cell cycle progression. Mechanistically, MFSD12 upregulation was found to activate PI3K signaling, and a PI3K inhibitor reversed the increase in cell proliferation endowed by MFSD12 upregulation. Clinically, high MFSD12 expression was positively associated with shorter overall survival (OS) and disease-free survival (DFS) in melanoma patients, and MFSD12 was an independent prognostic factor for OS and DFS in melanoma patients. Therapeutically, in vivo assays further confirmed that MFSD12 interference inhibited tumor growth and lung metastasis in melanoma. In conclusion, elevated MFSD12 expression promotes melanoma cell proliferation, and MFSD12 is a valuable prognostic biomarker and promising therapeutic target in melanoma.
The role of GLI-SOX2 signaling axis for gemcitabine resistance in pancreatic cancer Oncogene (IF 6.854) Pub Date : 2018-10-31 Yanfei Jia, Dongsheng Gu, Jun Wan, Beiqin Yu, Xiaoli Zhang, E. Gabriela Chiorean, Yunshan Wang, Jingwu Xie
Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.
Correction: Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis Oncogene (IF 6.854) Pub Date : 2018-10-30 Y. Patel, M. Soni, A. Awgulewitsch, M. J. Kern, S. Liu, N. Shah, U. P. Singh, H. Chen
Correction: Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis Correction: Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis, Published online: 30 October 2018; doi:10.1038/s41388-018-0559-7 Correction: Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis
IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma Oncogene (IF 6.854) Pub Date : 2018-10-27 Y. Liu, F. Li, Y. T. Yang, X. D. Xu, J. S. Chen, T. L. Chen, H. J. Chen, Y. B. Zhu, J. Y. Lin, Y. Li, X. M. Xie, X. L. Sun, Y. Q. Ke
Vasculogenic mimicry (VM) refers to the fluid-conducting channels formed by aggressive tumor cells rather than endothelial cells (EC) with elevated expression of genes associated with vascularization. VM has been considered as one of the reasons that glioblastoma becomes resistant to anti-VEGF therapy. However, the molecular basis underlying VM formation remains unclear. Here we report that the insulin-like growth factor–binding protein 2 (IGFBP2) acts as a potent factor to enhance VM formation in glioma. Evidence showed that elevated IGFBP2 expression was positively related with VM formation in patients with glioma. Enforced expression of IGFBP2 increased network formation of glioma cells in vitro by activating CD144 and MMP2 (Matrix Metalloproteinase 2). U251 cells with stable knockdown of IGFBP2 led to decreased VM formation and tumor progression in orthotopic mouse model. Mechanistically, IGFBP2 interacts with integrin α5 and β1 subunits and augments CD144 expression in a FAK/ERK pathway-dependent manner. Luciferase reporter and ChIP assay suggested that IGFBP2 activated the transcription factor SP1, which could bind to CD144 promoter. Thus, IGFBP2 acts as a stimulator of VM formation in glioma cells via enhancing CD144 and MMP2 expression.
Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53 Oncogene (IF 6.854) Pub Date : 2018-10-26 Luca Di Leo, Rolando Vegliante, Fabio Ciccarone, Illari Salvatori, Manuel Scimeca, Elena Bonanno, Andrea Sagnotta, Gian Luca Grazi, Katia Aquilano, Maria Rosa Ciriolo
Metabolic reprogramming is a typical feature of cancer cells aimed at sustaining high-energetic demand and proliferation rate. Here, we report clear-cut evidence for decreased expression of the adipose triglyceride lipase (ATGL), the first and rate-limiting enzyme of triglyceride hydrolysis, in both human and mouse-induced hepatocellular carcinoma (HCC). We identified metabolic rewiring as major outcome of ATGL overexpression in HCC-derived cell lines. Indeed, ATGL slackened both glucose uptake/utilization and cell proliferation in parallel with increased oxidative metabolism of fatty acids and enhanced mitochondria capacity. We ascribed these ATGL—downstream events to the activity of the tumor-suppressor p53, whose protein levels—but not transcript—were upregulated upon ATGL overexpression. The role of p53 was further assessed by abrogation of the ATGL-mediated effects upon p53 silencing or in p53-null hepatocarcinoma Hep3B cells. Furthermore, we provided insights on the molecular mechanisms governed by ATGL in HCC cells, identifying a new PPAR-α/p300 axis responsible for p53 acetylation/accumulation. Finally, we highlighted that ATGL levels confer different susceptibility of HCC cells to common therapeutic drugs, with ATGL overexpressing cells being more resistant to glycolysis inhibitors (e.g., 2-deoxyglucose and 3-bromopyruvate), compared to genotoxic compounds. Collectively, our data provide evidence for a previously uncovered tumor-suppressor function of ATGL in HCC, with the outlined molecular mechanisms shedding light on new potential targets for anticancer therapy.
Bclaf1 promotes angiogenesis by regulating HIF-1α transcription in hepatocellular carcinoma Oncogene (IF 6.854) Pub Date : 2018-10-26 Ying Wen, Xueqiong Zhou, Meiting Lu, Meiling He, Ye Tian, Lixia Liu, Mengnan Wang, Wenchong Tan, Yaotang Deng, Xushan Yang, Matthias P. Mayer, Fei Zou, Xuemei Chen
The development of hepatocellular carcinomas (HCC) depends on their local microenvironment and the induction of neovascularization is a decisive step in tumor progression, since the growth of solid tumors is limited by nutrient and oxygen supply. Hypoxia is the critical factor that induces transcription of the hypoxia inducible factor-1α (HIF-1α) encoding gene HIF1A and HIF-1α protein accumulation to promote angiogenesis. However, the basis for the transcriptional regulation of HIF1A expression in HCC is still unclear. Here, we show that Bclaf1 levels are highly correlated with HIF-1α levels in HCC tissues, and that knockdown of Bclaf1 in HCC cell lines significantly reduces hypoxia-induced HIF1A expression. Furthermore, we found that Bclaf1 promotes HIF1A transcription via its bZIP domain, leading subsequently to increased transcription of the HIF-1α downstream targets VEGFA, TGFB, and EPO that in turn promote HCC-associated angiogenesis and thus survival and thriving of HCC cells. Moreover, we demonstrate that HIF-1α levels and microvessel density decrease after the shRNA-mediated Bclaf1 knockdown in xenograft tumors. Finally, we found that Bclaf1 levels increase in hypoxia in a HIF-1α dependent manner. Therefore, our study identifies Bclaf1 as a novel positive regulator of HIF-1α in the hypoxic microenvironment, providing new incentives for promoting Bcalf1 as a potential therapeutic target for an anti-HCC strategy.
Adipose stromal cell targeting suppresses prostate cancer epithelial-mesenchymal transition and chemoresistance Oncogene (IF 6.854) Pub Date : 2018-10-25 Fei Su, Songyeon Ahn, Achinto Saha, John DiGiovanni, Mikhail G. Kolonin
Fat tissue, overgrowing in obesity, promotes the progression of various carcinomas. Clinical and animal model studies indicate that adipose stromal cells (ASC), the progenitors of adipocytes, are recruited by tumors and promote tumor growth as tumor stromal cells. Here, we investigated the role of ASC in cancer chemoresistance and invasiveness, the attributes of tumor aggressiveness. By using human cell co-culture models, we demonstrate that ASC induce epithelial-mesenchymal transition (EMT) in prostate cancer cells. Our results for the first time demonstrate that ASC interaction renders cancer cells more migratory and resistant to docetaxel, cabazitaxel, and cisplatin chemotherapy. To confirm these findings in vivo, we compared cancer aggressiveness in lean and obese mice grafted with prostate tumors. We show that obesity promotes EMT in cancer cells and tumor invasion into the surrounding fat tissue. A hunter-killer peptide D-CAN, previously developed for targeted ASC ablation, suppressed the obesity-associated EMT and cancer progression. Importantly, cisplatin combined with D-CAN was more effective than cisplatin alone in suppressing growth of mouse prostate cancer allografts and xenografts even in non-obese mice. Our data demonstrate that ASC promote tumor aggressiveness and identify them as a target of combination cancer therapy.
Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma Oncogene (IF 6.854) Pub Date : 2018-10-25 Hui Guo, Dongfeng Zeng, Hui Zhang, Taylor Bell, Jun Yao, Yang Liu, Shengjian Huang, Carrie J. Li, Elizabeth Lorence, Shouhao Zhou, Tiejun Gong, Changying Jiang, Makhdum Ahmed, Yixin Yao, Krystle J. Nomie, Liang Zhang, Michael Wang
The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton’s tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL.
Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic cancer via AMPK activation Oncogene (IF 6.854) Pub Date : 2018-10-24 Cheng Xu, Yunfei Wang, Qiu Tu, Zhiye Zhang, Mengrou Chen, James Mwangi, Yaxiong Li, Yang Jin, Xudong Zhao, Ren Lai
Pancreatic cancer remains one of the deadliest human cancers despite current advances in conventional therapeutics including surgery and adjuvant therapies. Here, we showed that LZ1, a peptide derived from a snake venom cathelicidin, significantly inhibited growth of pancreatic cancer cells by inducing autophagy-dependent cell death both in vitro and in vivo. The LZ1-induced cell death was blocked by pharmacological or genetic inhibition of autophagy. In orthotopic model of pancreatic cancer, systemic administration of LZ1 (1–4 mg/kg) exhibited remarkable antitumor efficacy, significantly prolonged mice survival, and showed negligible adverse effects by comparison with gemcitabine (20 mg/kg). Mechanistic studies revealed that LZ1 acts through binding to nucleolin, whose expression on cell surface is frequently increased in pancreatic cancer cells. LZ1 binding triggers degradation of surface-expressed nucleolin. This leads to activation of 5′-AMP kinase which results in suppression of mTORC1 activity and induction of autophagic flux. These data suggest that LZ1, targeting nucleolin–AMPK–autophagy axis, is a promising lead for the development of therapeutic agents against pancreatic cancer.
Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer Oncogene (IF 6.854) Pub Date : 2018-10-23 Steve Wagner, Georgios Vlachogiannis, Alexis De Haven Brandon, Melanie Valenti, Gary Box, Liam Jenkins, Caterina Mancusi, Annette Self, Floriana Manodoro, Ioannis Assiotis, Penny Robinson, Ritika Chauhan, Alistair G. Rust, Nik Matthews, Kate Eason, Khurum Khan, Naureen Starling, David Cunningham, Anguraj Sadanandam, Clare M. Isacke, Vladimir Kirkin, Nicola Valeri, Steven R. Whittaker
Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.
Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis Oncogene (IF 6.854) Pub Date : 2018-10-23 C. Probert, T. Dottorini, A. Speakman, S. Hunt, T. Nafee, A. Fazeli, S. Wood, J. E. Brown, V. James
The role of extracellular vesicles (EVs) as vehicles for cell-to-cell communication between a tumour and its environment is a relatively new concept. The hypothesis that EVs may be critical in co-opting tissues by tumours to generate distant metastatic niches is particularly pertinent to prostate cancer (PCa), where metastatic-tropism to bone predominates over other tissue types. The potential role of EVs as a means of communication between PCa cells and cells of the bone stroma such as osteoblasts, is yet to be fully explored. In this study, we demonstrate that PCa cell EVs both enhance osteoblast viability and produce a significantly more supportive growth environment for PCa cells when grown in co-culture with EV-treated osteoblasts (p < 0.005). Characterisation of the RNA cargo of EVs produced by the bone-metastatic PCa cell line PC3, highlights the EV-RNA cargo is significantly enriched in genes relating to cell surface signalling, cell–cell interaction, and protein translation (p < 0.01). Using novel techniques to track RNA, we demonstrate the delivery of a set of PCa-RNAs to osteoblast via PCa-EVs and show the effect on osteoblast endogenous transcript abundance. Taken together, by using proof-of-concept studies we demonstrate for the first time the contribution of the RNA element of the PCa EV cargo, providing evidence to support PCa EV communication via RNA molecules as a potential novel route to mediate bone metastasis. We propose targeting PCa EVs could offer a potentially important preventative therapy for men at risk of metastatic PCa.
A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma Oncogene (IF 6.854) Pub Date : 2018-10-23 Cheng Wang, Yayun Gu, Erbao Zhang, Kai Zhang, Na Qin, Juncheng Dai, Meng Zhu, Jia Liu, Kaipeng Xie, Yue Jiang, Xuejiang Guo, Mingxi Liu, Guangfu Jin, Hongxia Ma, Tao Jiang, Rong Yin, Yankai Xia, Li Liu, Shouyu Wang, Bin Shen, Ran Huo, Lin Xu, Jiahao Sha, Bin Qu, Hongbing Shen, Zhibin Hu
Our previous work found cancer-testis (CT) genes as a new source of epi-driver candidates of cancer. LIN28B was a CT gene, but the “driver” ability and the activation mechanism in lung adenocarcinoma (LUAD) remain unclear. We observed that LIN28B expression was restricted in testis. It was re-activated in LUAD patients without known genomic alterations in oncogenes and was related to poorer survival. In vitro and In vivo experiments confirmed that the activation of LIN28B could promote the proliferation and metastasis of LUAD cells and can influence cell cycle, DNA damage repair, and genome instability. In addition to the known let-7-LIN28B regulation loop, our results further revealed a let-7-independent Cis-regulator of LIN28B: LIN28B-AS1. LIN28B-AS1 is a CT long non-coding RNA (CT-lncRNA). It altered the messenger RNA stability of LIN28B by directly interacting with another CT protein IGF2BP1 but not with LIN28B and constituted a novel regulation network. In sum, we identify that LIN28B is an “epi-driver” of LUAD and clarify a new lncRNA-activated mechanism of LIN28B, which provide new candidate targets for precise anticancer therapy in the future.
Regulation of human glioma cell migration, tumor growth, and stemness gene expression using a Lck targeted inhibitor Oncogene (IF 6.854) Pub Date : 2018-10-23 J. P. Zepecki, K. M. Snyder, M. M. Moreno, E. Fajardo, A. Fiser, J. Ness, A. Sarkar, S. A. Toms, N. Tapinos
Migration of human glioma cells (hGCs) within the brain parenchyma makes glioblastoma one of the most aggressive and lethal tumors. Studies of the cellular and molecular mechanisms underlying hGC migration are hindered by the limitations of existing glioma models. Here we developed a dorsal root ganglion axon-oligodendrocyte-hGC co-culture to study in real time the migration and interaction of hGCs with their microenvironment. hGCs interact with myelinated and non-myelinated axons through the formation of pseudopodia. Isolation of pseudopodia-localized polysome-bound RNA reveals transcripts of Lck, Paxillin, Crk-II, and Rac1 that undergo local translation. Inhibition of Lck phosphorylation using a small-molecule inhibitor (Lck-I), blocks the phosphorylation of Paxillin and Crk-II, the formation of pseudopodia and the migration of hGCs. In vivo intraventricular administration of the Lck-I using an orthotopic xenograft glioma model, results in statistically significant inhibition of tumor size and significant down-regulation of Nanog-targeted genes, which are associated with glioblastoma patient survival. Moreover, treatment of human glioma stem cells (hGSCs) with Lck-I, results in significant inhibition of self-renewal and tumor-sphere formation. The involvement of Lck in different levels of glioma malignant progression, such as migration, tumor growth, and regulation of cancer stemness, makes Lck a potentially important therapeutic target for human glioblastomas.
Loss of Stat6 affects chromatin condensation in intestinal epithelial cells causing diverse outcome in murine models of inflammation-associated and sporadic colon carcinogenesis Oncogene (IF 6.854) Pub Date : 2018-10-23 Tiago De Oliveira, Mallika Ramakrishnan, Michaela A. Diamanti, Paul K. Ziegler, Frank Brombacher, Florian R. Greten
While great advances have been achieved regarding the genetic basis of colorectal cancer, the complex role of cell–cell communication and cytokine-induced signaling during its pathogenesis remains less understood. Signal transducer and activator of transcription 6 (Stat6) is the main transcription factor of interleukin-4 (IL-4) signaling and its participation in the development of various tumor types has been already reported. Here we aimed to examine the contribution of Stat6 in intestinal epithelial cells (IEC) in mouse models of intestinal carcinogenesis. Wild-type (WT), Stat6 knockout (Stat6−/−), and intestinal epithelial cell-specific IL-4Rα knockout (Il-4rαΔIEC) mice were subjected to colitis-associated (AOM/DSS) and colitis-independent (sporadic) carcinogenesis. IEC proliferation, apoptosis and RNA expression were evaluated by immunohistochemical, immunoblot, and RT-PCR analysis. We found that Stat6−/− mice developed more tumors in the colitis-associated carcinogenesis model. This was accompanied by a more pronounced inflammatory response during colitis and an elevated Stat3-dependent proliferation of IEC. Increased sensitivity to DSS-induced colitis was caused by elevated cell death in response to the initial carcinogen exposure as Stat6 deficiency led to increased chromatin compaction affecting DNA damage response in IEC upon treatment with alkylating agents independently of IL-4Rα engagement. Thus, loss of Stat6 caused more severe colitis and increased tumor load, however loss-of-initiated Stat6−/− IEC prevented tumor formation in the absence of overt inflammation. Our data unravel unexpected IL-4-independent functions of Stat6 in chromatin compaction in intestinal epithelial cells ultimately providing both tumor suppressive as well as tumor promoting effects in different models of intestinal tumorigenesis.
K120R mutation inactivates p53 by creating an aberrant splice site leading to nonsense-mediated mRNA decay Oncogene (IF 6.854) Pub Date : 2018-10-22 Seo-Young Lee, Jung-Hyun Park, Sangkyun Jeong, Bu-Yeo Kim, Yong-Kook Kang, Yang Xu, Sun-Ku Chung
The point mutation that substitutes lysine with arginine at position 120 of human p53 has been characterized as a missense mutation. The K120R mutation renders the p53 protein disabled for acetylation and, as a result, defective for apoptotic function, which provides a mechanistic link between the missense mutation and tumorigenesis. However, we noticed the failures of tumorigenesis in mice with the mutation, and of the related studies to notice that it has arbitrarily reflected in amino acid change through a sequence modification (AGA) of the original tumor mutation (AGG) by codon degeneracy. Unlike this modified version, we also discovered a novel splicing site the original mutation, TP53 c.359A>G, may induce. Using a human induced pluripotent stem cell line that was engineered to be homozygous for the original mutation, we here identified that the accidental splicing site generates a defective transcript variant with a frame-shifted premature termination codon which is subjected to nonsense-mediated mRNA decay. The authentic splicing still occurs but in extremely low amounts. Taken together, this mutation causes depletion of cellular p53 via defective mRNA, suggesting a new link to tumorigenesis.
Targeting colon cancer with the novel STAT3 inhibitor bruceantinol Oncogene (IF 6.854) Pub Date : 2018-10-22 Ning Wei, Jun Li, Cheng Fang, Jin Chang, Vasiliki Xirou, Nick K. Syrigos, Benjamin J. Marks, Edward Chu, John C. Schmitz
STAT3, a transcriptional mediator of oncogenic signaling, is constitutively active in ~70% of human cancers. The development of STAT3 inhibitors remains an active area of research as no inhibitors have yet to be approved for the treatment of human cancer. Herein, we revealed that bruceantinol (BOL) is a novel STAT3 inhibitor demonstrating potent antitumor activity in in vitro and in vivo human colorectal cancer (CRC) models. BOL strongly inhibited STAT3 DNA-binding ability (IC50 = 2.4 pM), blocked the constitutive and IL-6-induced STAT3 activation in a dose- and time-dependent manner, and suppressed transcription of STAT3 target genes encoding anti-apoptosis factors (MCL-1, PTTG1, and survivin) and cell-cycle regulators (c-Myc). Structure–activity relationship studies demonstrated that the C15 side chain on BOL affected its ability to bind STAT3. Administration of 4 mg/kg BOL significantly inhibited CRC tumor xenografts [p < 0.001], but no effect was observed in a STAT3−/− tumor model. Additional studies showed that BOL effectively sensitized MEK inhibitors through repression of p-STAT3 and MCL-1 induction, known resistance mechanisms of MEK inhibition. Taken together, our findings suggest BOL is a novel therapeutic STAT3 inhibitor that can be used either alone or in combination with MEK inhibitors for the treatment of human CRC.
Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer Oncogene (IF 6.854) Pub Date : 2018-10-22 Tracy L. Leong, Velimir Gayevskiy, Daniel P. Steinfort, Marc R. De Massy, Alvaro Gonzalez-Rajal, Kieren D. Marini, Emily Stone, Venessa Chin, Adrian Havryk, Marshall Plit, Louis B. Irving, Barton R. Jennings, Rachael A. McCloy, W. Samantha N. Jayasekara, Muhammad Alamgeer, Vishal Boolell, Andrew Field, Prudence A. Russell, Beena Kumar, Daniel J. Gough, Anette Szczepny, Vinod Ganju, Fernando J. Rossello, Jason E. Cain, Anthony T. Papenfuss, Marie-Liesse Asselin-Labat, Mark J. Cowley, D. Neil Watkins
Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.
Rare type 1-like and type 2-like calreticulin mutants induce similar myeloproliferative neoplasms as prevalent type 1 and 2 mutants in mice Oncogene (IF 6.854) Pub Date : 2018-10-19 Katte Rao Toppaldoddi, Maira da Costa Cacemiro, Olivier Bluteau, Barbara Panneau-Schmaltz, Amélie Pioch, Delphine Muller, Jean-Luc Villeval, Hana Raslova, Stefan N. Constantinescu, Isabelle Plo, William Vainchenker, Caroline Marty
Frameshift mutations in the calreticulin (CALR) gene are present in 30% of essential thrombocythemia and myelofibrosis patients. The two most frequent mutations are CALR del52 (type 1, approximately 60%) and CALR ins5 (type 2, around 30%), but many other rarer mutations exist accounting each for less than 2% of all CALR mutations. Most of them are structurally classified as type 1-like and type 2-like CALR mutations according to the absence or presence of a residual wild-type calcium-binding motif and the modification of the alpha-helix structure. Yet, several key questions remain unanswered, especially the reason of such low frequencies of these other mutations. In an attempt to investigate specific pathogenic differences between type 1-like and type 2-like CALR mutations and del52 and ins5, we modeled two type 1-like (del34 and del46) and one type 2-like (del19) mutations in cell lines and in mice. All CALR mutants constitutively activate JAK2 and STAT5/3/1 in a similar way in the presence of the thrombopoietin receptor (MPL) and induced cytokine-independent cell growth but to a lesser extent with rare mutants over time. This correlates with reduced expression levels of rare CALR mutants compared to del52 and ins5. Lethally irradiated mice that were engrafted with bone marrow transduced with the different CALR mutations developed thrombocytosis, but to a much lesser extent with ins5 and the type 2-like CALR mutation. In contrast to type 2-like mice, type 1-like mice developed marked myelofibrosis and splenomegaly 10 months after engraftment. Similar to del52, type 1-like CALR mutations induced an expansion at an early stage of hematopoiesis compared to ins5 and type 2-like mutation. Thus, type 1-like and type 2-like CALR mutants structurally and functionally resemble del52 and ins5 mutants, respectively.
Overexpression of cellular telomerase RNA enhances virus-induced cancer formation Oncogene (IF 6.854) Pub Date : 2018-10-19 Ahmed Kheimar, Jakob Trimpert, Nicole Groenke, Benedikt B. Kaufer
The telomerase RNA subunit (TR) is overexpressed in many tumors; however, the contribution of TR in cancer formation remains elusive. The most frequent clinically diagnosed cancer in the animal kingdom is caused by the highly oncogenic herpesvirus Marek’s disease virus (MDV). MDV encodes a TR (vTR) that plays an important role in virus-induced tumorigenesis and shares 88% sequence identity with its cellular homologue. To determine if the cellular TR possesses pro-oncogenic activity, we replaced vTR with the cellular homologue in the virus genome. Insertion of cellular TR resulted in a strong overexpression in virus infected cells, while virus replication was not affected. Strikingly, cellular TR promoted tumor formation as efficient as vTR, while tumorigenesis was severely impaired in the absence of vTR. Our data provide the first evidence that overexpression of cellular TR can contribute to tumor formation in vivo using this natural virus-host model for herpesvirus-induced oncogenesis.
CXCR7/CXCR4 heterodimer-induced histone demethylation: a new mechanism of colorectal tumorigenesis Oncogene (IF 6.854) Pub Date : 2018-10-18 Zhi-Yu Song, Feng Wang, Shu-Xiang Cui, Zu-Hua Gao, Xian-Jun Qu
Both chemokine receptors (CXCRs) 7 and 4 can facilitate immune cell migration and mediate a vast array of physiological and pathological events. Herein we report, in both human and animal studies, that these two CXCRs can form heterodimers in vivo and promote colorectal tumorigenesis through histone demethylation. Compared with adjacent non-neoplastic tissue, human colorectal cancer (CRC) tissue showed a significant higher expression of CXCR4 and CXCR7, which was colocalized in the cancer cell epithelium. The CXCR/CXCR4 heterodimerization was associated with increased histone demethylase JMJD2A. Villin-CXCR7-CXCR4 transgenic mice demonstrated a greater degree of exacerbated colitis and tumorigenesis than villin-CXCR7 and villin-CXCR4 mice. The CXCR7/CXCR4 heterodimerization also promoted APC mutation-driven colorectal tumorigenesis in APCMin/+/villin-CXCR7-CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear βarr1 recruitment and histone demethylase JMJD2A, leading to histone demethylation and resulting in transcription of inflammatory factors and oncogenes. This study uncovered a novel mechanism of colorectal tumorigenesis through the CXCR7/CXCR4 heterodimer-induced histone demethylation. Inhibition of CXCR7/CXCR4 heterodimer-induced histone demethylation could be an effective strategy for the prevention and treatment of colorectal cancer.
PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response Oncogene (IF 6.854) Pub Date : 2018-10-18 Srilatha Simhadri, Gabriele Vincelli, Yanying Huo, Sarah Misenko, Tzeh Keong Foo, Johanna Ahlskog, Claus S. Sørensen, Gregory G. Oakley, Shridar Ganesan, Samuel F. Bunting, Bing Xia
The G2/M checkpoint inhibits mitotic entry upon DNA damage, thereby preventing segregation of broken chromosomes and preserving genome stability. The tumor suppressor proteins BRCA1, PALB2 and BRCA2 constitute a BRCA1–PALB2–BRCA2 axis that is essential for homologous recombination (HR)-based DNA doublestrand break repair. Besides HR, BRCA1 has been implicated in both the initial activation and the maintenance of the G2/M checkpoint, while BRCA2 and PALB2 have been shown to be critical for its maintenance. Here we show that all three proteins can play a significant role in both checkpoint activation and checkpoint maintenance, depending on cell type and context, and that PALB2 links BRCA1 and BRCA2 in the checkpoint response. The BRCA1–PALB2 interaction can be important for checkpoint activation, whereas the PALB2–BRCA2 complex formation appears to be more critical for checkpoint maintenance. Interestingly, the function of PALB2 in checkpoint response appears to be independent of CHK1 and CHK2 phosphorylation. Following ionizing radiation, cells with disengaged BRCA1–PALB2 interaction show greatly increased chromosomal abnormalities due apparently to combined defects in HR and checkpoint control. These findings provide new insights into DNA damage checkpoint control and further underscore the critical importance of the proper cooperation of the BRCA and PALB2 proteins in genome maintenance.
TROY interacts with RKIP to promote glioma development Oncogene (IF 6.854) Pub Date : 2018-10-18 Xiujie Liu, Yinghui Bao, Wei Meng, Ping Yang, Yi An, Jie Ma, Yujie Tang, Zhigang Liu, Yan Lu, Jianfeng Zhou, Yong Zhang, Jifeng Feng, Xiaofei Gao, Zhida Su, Yingyan Pu, Cheng He
TROY is a component of the Nogo receptor complex and plays the key role in neuronal survival, migration, and differentiation. Here, we show the up-regulation of TROY in human glioma tissues and cells. Inhibition of TROY expression slowed glioma development in vivo and in vitro. Raf kinase inhibitor (RKIP) was found to interact with TROY. The physical interaction of TROY/RKIP was confirmed via co-immunoprecipitation (co-IP) assays. Furthermore, we found that the TROY/RKIP interaction was enhanced by fetal bovine serum (FBS) exposure, and TROY knockdown also led to down-regulation of NF-κB. Finally, disruption of the TROY/RKIP interaction using the TAT-TROY (234–371 aa) protein reduced the glioma development in xenografted mice. This suggests the TROY/RKIP interaction is a potential target for therapy of gliomas.
mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53 Oncogene (IF 6.854) Pub Date : 2018-10-18 Seung Hee Jung, Hyun Jung Hwang, Donghee Kang, Hyun A. Park, Hyung Chul Lee, Daecheol Jeong, Keunwook Lee, Heon Joo Park, Young-Gyu Ko, Jae-Seon Lee
Loss of PTEN, the major negative regulator of the PI3K/AKT pathway induces a cellular senescence as a failsafe mechanism to defend against tumorigenesis, which is called PTEN-loss-induced cellular senescence (PICS). Although many studies have indicated that the mTOR pathway plays a critical role in cellular senescence, the exact functions of mTORC1 and mTORC2 in PICS are not well understood. In this study, we show that mTOR acts as a critical relay molecule downstream of PI3K/AKT and upstream of p53 in PICS. We found that PTEN depletion induces cellular senescence via p53-p21 signaling without triggering DNA damage response. mTOR kinase, a major component of mTORC1 and mTORC2, directly binds p53 and phosphorylates it at serine 15. mTORC1 and mTORC2 compete with MDM2 and increase the stability of p53 to induce cellular senescence via accumulation of the cell cycle inhibitor, p21. In embryonic fibroblasts of PTEN-knockout mice, PTEN deficiency also induces mTORC1 and mTORC2 to bind to p53 instead of MDM2, leading to cellular senescence. These results collectively demonstrate for the first time that mTOR plays a critical role in switching cells from proliferation signaling to senescence signaling via a direct link between the growth-promoting activity of AKT and the growth-suppressing activity of p53.
ZNF185 is a p63 target gene critical for epidermal differentiation and squamous cell carcinoma development Oncogene (IF 6.854) Pub Date : 2018-10-18 Artem Smirnov, Anna Maria Lena, Angela Cappello, Emanuele Panatta, Lucia Anemona, Simone Bischetti, Margherita Annicchiarico-Petruzzelli, Alessandro Mauriello, Gerry Melino, Eleonora Candi
Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell–cell and cell–matrix adhesion programmes. However, limited knowledge exists on the relevant cell–cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell–cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell–cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.
NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease Oncogene (IF 6.854) Pub Date : 2018-10-15 Ebru Aydin, Alexander Hallner, Hanna Grauers Wiktorin, Anna Staffas, Kristoffer Hellstrand, Anna Martner
Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-KrasG12D × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-KrasG12D) were treated with Nα-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H2 receptors. M-KrasG12D mice developed myeloid leukemia comprising mature CD11b+Gr1+ myeloid cells that produced NOX2-derived ROS. Treatment of M-KrasG12D mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-KrasG12D mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2−/− × LSL-KrasG12D × Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer.
Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth Oncogene (IF 6.854) Pub Date : 2018-10-10 Karen McLean, Lijun Tan, Danielle E. Bolland, Lan G. Coffman, Luke F. Peterson, Moshe Talpaz, Nouri Neamati, Ronald J. Buckanovich
Ovarian carcinoma-associated mesenchymal stem cells (CA-MSC) produce not only high levels of interleukin-6 (IL6) but also the related cytokine leukemia inhibitory factor (LIF). IL6-mediated activation of STAT3 is implicated as a critical therapeutic target for cancer therapy. Less is known about the role of LIF, which can similarly activate STAT3, in ovarian cancer. We therefore sought to evaluate the tumorigenic effects of CA-MSC paracrine LIF signaling and the redundancy of IL6 and LIF in activating ovarian cancer STAT3 mediated cancer growth. As expected, we found that both IL6 and LIF induce STAT3 phosphorylation in tumor cells. In addition, both IL6 and LIF increased the percentage of ALDH+ ovarian cancer stem-like cells (CSC). Supporting redundancy of function by the two cytokines, CA-MSC induced STAT3 phosphorylation and increased cancer cell “stemness”. This effect was not inhibited by LIF or IL6 blocking antibodies alone, but was prevented by dual IL6/LIF blockade or JAK2 inhibition. Similarly, small hairpin RNA (shRNA)-mediated reduction of IL6 or LIF in CA-MSC partially decreased but could not completely abrograte the ability of CA-MSC to induce STAT3 phosphorylation and stemness. Importantly, the in vivo pro-tumorigenic effect of CA-MSC is abrogated by dual blockade with the JAK2 inhibitor ruxolitinib to a much greater extent than treatment with anti-IL6 or anti-LIF antibody alone. Ruxolitinib treatment also improves survival in the immunocompetent ovarian cancer mouse model system with ID8 tumor cells plus MSC. Ruxolitinib-treated tumors in both the immunocompromised and immunocompetent animal models demonstrate decreased phospho-STAT3, indicating on-target activity. In conclusion, CA-MSC activate ovarian cancer cell STAT3 signaling via IL6 and LIF and increase tumor cell stemness. This functional redundancy suggests that therapeutic targeting of a single cytokine may be less effective than strategies such as dual inhibitor therapy or targeting shared downstream factors of the JAK/STAT pathway.
Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis Oncogene (IF 6.854) Pub Date : 2018-10-10 Hailong Zhang, Yanli Wang, Jinzhuo Dou, Yanmin Guo, Jianfeng He, Lian Li, Xiaojia Liu, Ran Chen, Rong Deng, Jian Huang, Ruiyu Xie, Xian Zhao, Jianxiu Yu
Argonaute2 (AGO2) is an effector of small RNA mediated gene silencing. Increasing evidence show that post-translational modifications of AGO2 can change miRNA activity at specific or global levels. Among the six mature miRNAs that are encoded by miR-17-92, miR-19b1 is the most powerful to exert the oncogenic properties of the entire cluster. Here we identify that AGO2 can be acetylated by P300/CBP and deacetylated by HDAC7, and that acetylation occurs at three sites K720, K493, and K355. Mutation of K493R/K720R, but not K355R at AGO2, inhibits miR-19b biogenesis. We demonstrate that acetylation of AGO2 specifically increases its recruiting pre-miR-19b1 to form the miPDC (miRNA precursor deposit complex), thereby to enhance miR-19b maturation. The motif UGUGUG in the terminal-loop of pre-miR-19b1, as a specific processing feature that is recognized and bound by acetylated AGO2, is essential for the assembly of miRISC (miRNA-induced silencing complex) loading complex. Analyses on public clinical data, xenograft mouse models, and IHC and ISH staining of lung cancer tissues, further confirm that the high levels of both AGO2 acetylation and miR-19b correlate with poor prognosis in lung cancer patients. Our finding reveals a novel function of AGO2 acetylation in increasing oncogenic miR-19b biogenesis and suggests that modulation of AGO2 acetylation has potential clinical implications.
Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia Oncogene (IF 6.854) Pub Date : 2018-10-10 Phyllis S. Y. Chong, Jianbiao Zhou, Jing-Yuan Chooi, Zit-Liang Chan, Sabrina Hui Min Toh, Tuan Zea Tan, Sheena Wee, Jayantha Gunaratne, Qi Zeng, Wee-Joo Chng
Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.
IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells Oncogene (IF 6.854) Pub Date : 2018-10-10 Masahiro Shimizu, Nobuyuki Tanaka
Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.
Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment Oncogene (IF 6.854) Pub Date : 2018-10-10 Sandra Muñoz-Galván, Antonio Lucena-Cacace, Marco Perez, Daniel Otero-Albiol, Julian Gomez-Cambronero, Amancio Carnero
Cancer cells are in continuous communication with the surrounding microenvironment and this communication can affect tumor evolution. In this work, we show that phospholipase D2 (PLD2) was overexpressed in colon tumors and is secreted by cancer cells, inducing senescence in neighboring fibroblasts. This occurs through its lipase domain. Senescence induced by its product, phosphatidic acid, leads to a senescence-associated secretory phenotype (SASP) able to increase the stem properties of cancer cells. This increase in stemness occurs by Wnt pathway activacion. This closes a feedback loop in which senescence acts as a crosspoint for the generation of CSCs mediated by phospholipid metabolism. We also demonstrate the connexion of both phenomena in mouse models in vivo showing that a high PLD2 expression increased stemness and tumorigenesis. Thus, the patients with colon cancer show high levels of PLD2 and SASP factor genes expression correlating with Wnt pathway activation. Therefore, we demonstrate that tumor cell-secreted PLD2 contributes to tumor development by modifying the microenvironment, making it a possible therapeutic target for cancer treatment. This mechanism may also explain the high levels of Wnt pathway activation in colon cancer.
Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition Oncogene (IF 6.854) Pub Date : 2018-10-10 H. Rudolf de Boer, Martin Pool, Esméé Joosten, Marieke Everts, Douwe F. Samplonius, Wijnand Helfrich, Harry J. M. Groen, Suzanne van Cooten, Fabrizia Fusetti, Rudolf S. N. Fehrmann, Elisabeth G. E. de Vries, Marcel A. T. M. van Vugt
Tumor responses to cancer therapeutics are generally monitored every 2–3 months based on changes in tumor size. Dynamic biomarkers that reflect effective engagement of targeted therapeutics to the targeted pathway, so-called “effect sensors”, would fulfill a need for non-invasive, drug-specific indicators of early treatment effect. Using a proteomics approach to identify effect sensors, we demonstrated MUC1 upregulation in response to epidermal growth factor receptor (EGFR)-targeting treatments in breast and lung cancer models. To achieve this, using semi-quantitative mass spectrometry, we found MUC1 to be significantly and durably upregulated in response to erlotinib, an EGFR-targeting treatment. MUC1 upregulation was regulated transcriptionally, involving PI3K-signaling and STAT3. We validated these results in erlotinib-sensitive human breast and non-small lung cancer cell lines. Importantly, erlotinib treatment of mice bearing SUM149 xenografts resulted in increased MUC1 shedding into plasma. Analysis of MUC1 using serial blood sampling may therefore be a new, relatively non-invasive tool to monitor early and drug-specific effects of EGFR-targeting therapeutics.
Hsp90ab1 stabilizes LRP5 to promote epithelial–mesenchymal transition via activating of AKT and Wnt/β-catenin signaling pathways in gastric cancer progression Oncogene (IF 6.854) Pub Date : 2018-10-10 Huanan Wang, Guangxu Deng, Meiling Ai, Zhijun Xu, Tingyu Mou, Jiang Yu, Hao Liu, Shuang Wang, Guoxin Li
Hsp90ab1 is upregulated in numerous solid tumors, which is thought to induce the angiogenesis and promote cancer metastasis. However, it’s actions in gastric cancer (GC) has not been exhibited. In this study, Hsp90ab1 was demonstrated to be overexpressed and correlated with the poor prognosis, proliferation and invasion of GC. Ectopic expression of Hsp90ab1 promoted the proliferation and metastasis of GC cells both in vitro in cell line models of GC and in vivo using two different xenograft mouse models, while opposite effects were observed in Hsp90ab1 silenced cells. Moreover, the underlining molecular mechanism was explored by the co-immunoprecipitation, immunofluorescence, GST pull-down and in vitro ubiquitination assay. Namely, Hsp90ab1 exerted these functions via the interaction of LRP5 and inhibited ubiquitin-mediated degradation of LRP5, an indispensable coreceptor of the Wnt/β-catenin signaling pathway. In addition, the crosstalk between Hsp90ab1 and LRP5 contributed to the upregulation of multiple mesenchymal markers, which are also targets of Wnt/β-catenin. Collectively, this study uncovers the details of the Hsp90ab1-LRP5 axis, providing novel insights into the role and mechanism of invasion and metastasis in GC.
Family-based germline sequencing in children with cancer Oncogene (IF 6.854) Pub Date : 2018-10-10 Michaela Kuhlen, Julia Taeubner, Triantafyllia Brozou, Dagmar Wieczorek, Reiner Siebert, Arndt Borkhardt
The discovery of cancer-predisposing syndromes (CPSs) using next-generation sequencing (NGS) technologies is of increasing importance in pediatric oncology with regard to diagnosis, treatment, surveillance, family counselling and research. Recent studies indicate that a considerable percentage of childhood cancers are associated with CPSs. However, the ratio of CPSs that are caused by inherited vs. de novo mutations (DNMs), the risk of recurrence, and even the total number of genes, which should be considered as a true cancer-predisposing gene, are still unknown. In contrast to sequencing only single index patients, family-based NGS of the germline is a very powerful tool for providing unique insights into inheritance patterns (e.g., DNMs, parental mosaicism) and types of aberrations (e.g., SNV, CNV, indels, SV). Furthermore, functional perturbations of key cancer pathways (e.g., TP53, FA/BRCA) by at least two co-inherited heterozygous digenic mutations from each parent and currently unrecognized rare variants and unmeasured genetic interactions between common and rare variants may be a widespread genetic phenomenon in the germline of affected children. Therefore, family-based trio sequencing has the potential to reveal a striking new landscape of inheritance in childhood cancer and to facilitate the integration and efforts of individualized treatment strategies, including personalized and preventive medicine and cancer surveillance programs. Consequently, cancer genetics is becoming an increasingly common approach in modern oncology, so trio-sequencing should also be routinely integrated into pediatric oncology.
An HER3-targeting antibody–drug conjugate incorporating a DNA topoisomerase I inhibitor U3-1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC Oncogene (IF 6.854) Pub Date : 2018-10-09 Kimio Yonesaka, Naoki Takegawa, Satomi Watanabe, Koji Haratani, Hisato Kawakami, Kazuko Sakai, Yasutaka Chiba, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Kazuto Nishio, Kazuhiko Nakagawa
EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody–drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.
The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2 Oncogene (IF 6.854) Pub Date : 2018-10-09 My-Lan Kha, Lisa Hesse, Florian Deisinger, Bence Sipos, Christoph Röcken, Alexander Arlt, Susanne Sebens, Ole Helm, Heiner Schäfer
Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.
XIAP facilitates breast and colon carcinoma growth via promotion of p62 depletion through ubiquitination-dependent proteasomal degradation Oncogene (IF 6.854) Pub Date : 2018-10-01 Xing Huang, Xiao-nan Wang, Xiao-dong Yuan, Wen-yong Wu, Peter E. Lobie, Zhengsheng Wu
X-linked inhibitor of apoptosis protein (XIAP) possesses a critical role in promotion of cell survival and maintenance of cellular homeostasis. In cancer, elevated XIAP expression has been associated with malignancy, poor prognosis, and treatment resistance. However, the underlying mechanisms of these effects remain unclear. XIAP has previously been proposed to promote tumor growth through suppression of autophagy. In this study, we examined the expression of XIAP and p62, two critical mediators of autophagy, in breast and colon cancer. We observed a negative correlation between XIAP and p62 expression in normal and cancer tissues of breast and colon, and that the ratio of XIAP and p62 expression determines the cancer phenotype. In vitro, we observed that XIAP interacted with p62 and also that XIAP depletion resulted in increased expression of p62. XIAP functioned as an ubiquitination E3 ligase towards p62 and suppressed p62 expression through ubiquitin–proteasomal degradation. Furthermore, XIAP enhanced cancer cell proliferation, viability, and colony formation in vitro via suppression of p62. In addition, we demonstrated that XIAP-enhanced tumor growth is dependent on depletion of p62 in vivo. Herein, we have therefore delineated a novel mechanism by which XIAP contributes to development and progression of breast and colon carcinoma.
CBAP modulates Akt-dependent TSC2 phosphorylation to promote Rheb-mTORC1 signaling and growth of T-cell acute lymphoblastic leukemia Oncogene (IF 6.854) Pub Date : 2018-09-28 Yun-Jung Chiang, Wei-Ting Liao, Kun-Chin Ho, Shih-Hao Wang, Yu-Guang Chen, Ching-Liang Ho, Shiu-Feng Huang, Lee-Yung Shih, Hsin-Fang Yang-Yen, Jeffrey Jong-Young Yen
High-frequency relapse remains a clinical hurdle for complete remission of T-cell acute lymphoblastic leukemia (T-ALL) patients, with heterogeneous dysregulated signaling profiles—including of Raf-MEK-ERK and Akt-mTORC1-S6K signaling pathways—recently being implicated in disease outcomes. Here we report that GM-CSF/IL-3/IL-5 receptor common β-chain-associated protein (CBAP) is highly expressed in human T-ALL cell lines and many primary tumor tissues and is required to bolster leukemia cell proliferation in tissue culture and for in vivo leukemogenesis in a xenograft mouse model. Downregulation of CBAP markedly restrains expansion of leukemia cells and alleviates disease aggravation of leukemic mice. Transcriptomic profiling and molecular biological analyses suggest that CBAP acts upstream of Ras and Rac1, and functions as a modulator of both Raf-MEK–ERK and Akt-mTORC1 signaling pathways to control leukemia cell growth. Specifically, CBAP facilitated Akt-dependent TSC2 phosphorylation in cell-based assays and in vitro analysis, decreased lysosomal localization of TSC2, and elevated Rheb-GTP loading and subsequent activation of mTORC1 signaling. Taken together, our findings reveal a novel oncogenic contribution of CBAP in T-ALL leukemic cells, in addition to its original pro-apoptotic function in cytokine-dependent cell lines and primary hematopoietic cells, by demonstrating its functional role in the regulation of Akt-TSC2-mTORC1 signaling for leukemia cell proliferation. Thus, CBAP represents a novel therapeutic target for many types of cancers and metabolic diseases linked to PI3K-Akt-mTORC1 signaling.
ASPM promotes prostate cancer stemness and progression by augmenting Wnt−Dvl-3−β-catenin signaling Oncogene (IF 6.854) Pub Date : 2018-09-28 Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan, Wen-Ying Liao, Chih-Pin Chuu, Wei-Yu Chen, Chi-Rong Li, Ching-Yu Lin, Shu-Pin Hwang, Li-Tzong Chen, Kelvin K. Tsai
Recurrent and hormone-refractory prostate cancer (PCA) exhibits aggressive behaviors while current therapeutic approaches show little effect of prolonging the survival of patients with PCA. Thus, a deeper understanding of the patho-molecular mechanisms underlying the disease progression in PCA is crucial to identify novel diagnostic and/or therapeutic targets to improve the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here, we report that a novel Wnt co-activator ASPM (abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation by augmenting the Wnt-β-catenin signaling in PCA. ASPM expression is incrementally upregulated in primary and metastatic PCA, implicating its potential role in PCA progression. Consistently, downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH+ CSCs and inhibited cancer stemness and tumorigenicity. Mechanistically, ASPM interacts with disheveled-3 (Dvl-3), a cardinal upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing its protein stability and enabling the Wnt-induced β-catenin transcriptional activity in PCA cells. In keeping with the role of ASPM as a CSC-regulator, ASPM co-localizes with ALDH in PCA tissues and its expression exhibits high intra-tumoral heterogeneity. The proportion of high-ASPM-expressing cells in the tumor inversely correlates with the relapse-free survival of PCA patients. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of Wnt signaling and cancer stemness in PCA, which has important clinical and therapeutic significance.
The interaction of Lin28A/Rho associated coiled-coil containing protein kinase2 accelerates the malignancy of ovarian cancer Oncogene (IF 6.854) Pub Date : 2018-09-28 Yancheng Zhong, Sheng Yang, Wei Wang, Pingpin Wei, Shiwei He, Haotian Ma, Juan Yang, Qian Wang, Lanqin Cao, Wei Xiong, Ming Zhou, Guiyuan Li, Cijun Shuai, Shuping Peng
Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignant diseases, however, the molecular mechanism of ovarian cancer is not well defined. Previous studies have found that RNA binding protein Lin28A is a key factor of maintain the pluripotency of stem cells, and it is positively correlated with the degree of several cancers (breast, prostate, liver cancer, etc). Our previous study shows that Lin28A is highly expressed in OC tissues and is involved in the regulation of OC cell biological behavior. In this study, we confirmed that high expression of Lin28A promoted the survival, invasion, metastasis, and inhibited the apoptosis of OC cells. Lin28A interacts with Rho associated coiled-coil containing protein kinase2 (ROCK2) but not ROCK1 and upregulates the expression of ROCK2 in OC cells. The binding sites of each other were identified by truncated mutations and Immuno-precipitaion (IP) assay. After knock down of ROCK2 in cells with high expression of Lin28A, the survival, invasion, metastasis was significantly inhibited and early apoptosis was increased in OC cells and OC xenograft in nude mice. Our experimental data also showed that knock down of ROCK2 but not ROCK1 inhibited the invasion by decreasing the expression of N-cadherin, Slug, β-catenin and increasing ZO-1 expression. Simultaneously, knock down of ROCK2 induced cell apoptosis by increasing cleaved Caspase-9,cleaved Caspase-7, and cleaved Caspase-3. Taken together, Lin28A regulated the biological behaviors in OC cells through ROCK2 and the interaction of Lin28A/ROCK2 may be a new target for diagnosis and gene therapy of OC.
Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation Oncogene (IF 6.854) Pub Date : 2018-09-27 J. Zhu, C. Zhao, A. Kharman-Biz, T. Zhuang, P. Jonsson, N. Liang, C. Williams, C.-Y. Lin, Y. Qiao, K. Zendehdel, S. Strömblad, E. Treuter, K. Dahlman-Wright
Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation, Published online: 27 September 2018; doi:10.1038/s41388-018-0502-y Correction: The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation
C/EBPδ links IL-6 and HIF-1 signaling to promote breast cancer stem cell-associated phenotypes Oncogene (IF 6.854) Pub Date : 2018-09-27 Kuppusamy Balamurugan, Daniel Mendoza-Villanueva, Shikha Sharan, Glenn H. Summers, Lacey E. Dobrolecki, Michael T. Lewis, Esta Sterneck
To improve cancer patient outcome significantly, we must understand the mechanisms regulating stem-like cancer cells, which have been implicated as a cause of metastasis and treatment resistance. The transcription factor C/EBPδ can exhibit pro- and anti-tumorigenic activities, but the mechanisms underlying the complexity of its functions are poorly understood. Here we identify a role for breast cancer cell intrinsic C/EBPδ in promoting phenotypes that have been associated with cancer stem cells (CSCs). While C/EBPδ expression is not abundant in most metastatic breast cancers, our data support a pro-tumorigenic role of C/EBPδ when expressed in subsets of tumor cells and/or through transient activation by the tumor microenvironment or loss of substrate adhesion. Using genetic mouse models and human breast cancer cell lines, we show that deletion or depletion of C/EBPδ reduced expression of stem cell factors and stemnness markers, sphere formation and self-renewal, along with growth of tumors and established experimental metastases in vivo. C/EBPδ is also known as a mediator of the innate immune response, which is enhanced by hypoxia and interleukin-6 (IL-6) signaling, two conditions that also play important roles in cancer progression. Our mechanistic data reveal C/EBPδ as a link that engages two positive feedback loops, in part by directly targeting the IL-6 receptor (IL6RA) gene, and, thus, amplifying IL-6 and HIF-1 signaling. This study provides a molecular mechanism for the synergism of tumor microenvironmental conditions in cancer progression with potential implications for the targeting of CSCs.
CD163, a novel therapeutic target, regulates the proliferation and stemness of glioma cells via casein kinase 2 Oncogene (IF 6.854) Pub Date : 2018-09-26 Taoliang Chen, Jiansheng Chen, Yubo Zhu, Yan Li, Yun Wang, Huajian Chen, Jihui Wang, Xiao Li, Yang Liu, Baisheng Li, Xinlin Sun, Yiquan Ke
Glioma is a devastating cancer with a dismal prognosis and there is an urgent need to discover novel glioma-specific antigens for glioma therapy. Previous studies have identified CD163-positive tumour cells in certain solid tumours, but CD163 expression in glioma remains unknown. In this study, via an analysis of public datasets, we demonstrated that CD163 overexpression in glioma specimens correlated with an unfavourable patient prognosis. CD163 expression was increased in glioma cells, especially primary glioma cells. The loss of CD163 expression inhibited both cell cycle progression and the proliferation of glioblastoma multiforme (GBM) cell lines and primary glioma cells. CD163 interacted directly with casein kinase 2 (CK2) and CD163 silencing reduced AKT/GSK3β/β-catenin/cyclin D1 pathway activity via CK2. Moreover, CD163 was upregulated in CD133-positive glioma stem cells (GSCs), and CD163 downregulation decreased the expression of GSC markers, including CD133, ALDH1A1, NANOG and OCT4. The knockdown of CD163 impaired GSC stemness by inhibiting the CK2/AKT/GSK3β/β-catenin pathway. Finally, a CD163 antibody successfully induced complement-dependent cytotoxicity against glioma cells. Our findings indicate that CD163 contributes to gliomagenesis via CK2 and provides preclinical evidence that CD163 and the CD163 pathway might serve as a therapeutic target for glioma.
E2F1 and E2F7 differentially regulate KPNA2 to promote the development of gallbladder cancer Oncogene (IF 6.854) Pub Date : 2018-09-25 Shanshan Xiang, Zheng Wang, Yuanyuan Ye, Fei Zhang, Huaifeng Li, Yang Yang, Huijie Miao, Haibin Liang, Yijian Zhang, Lin Jiang, Yunping Hu, Lei Zheng, Xiyong Liu, Yingbin Liu
Karyopherin alpha 2 (KPNA2) is a nuclear import factor that is elevated in multiple cancers. However, its molecular regulation at the transcriptional levels is poorly understood. Here we found that KPNA2 was significantly upregulated in gallbladder cancer (GBC), and the increased levels were correlated with short survival of patients. Gene knocking down of KPNA2 inhibited tumor cell proliferation and migration in vitro as well as xenografted tumor development in vivo. A typical transcription factor E2F1 associated with its DNA-binding partner DP1 bond to the promoter region of KPNA2 and induced KPNA2 expression. In contrast, an atypical transcription factor E2F7 competed against DP1 and blocked E2F1-induced KPNA2 gene activation. Mutation of the dimerization residues of E2F7 or DNA-binding domain of E2F1 abolished the suppressive effects of E2F7 on KPNA2 gene expression. In addition, KPNA2 mediated nuclear localization of E2F1 and E2F7, where they in turn controlled KPNA2 expression. Taken together, our data provided mechanistic insights into divergently transcriptional regulation of KPNA2, thus pointing to KPNA2 as a potential target for cancer therapy.
BRAF fusions identified in melanomas have variable treatment responses and phenotypes Oncogene (IF 6.854) Pub Date : 2018-09-25 Jacqueline A. Turner, Judson G. T. Bemis, Stacey M. Bagby, Anna Capasso, Betelehem W. Yacob, Tugs-Saikhan Chimed, Robert Van Gulick, Hannah Lee, Richard Tobin, John J. Tentler, Todd Pitts, Martin McCarter, William A. Robinson, Kasey L. Couts
Oncogenic BRAF fusions have emerged as an alternate mechanism for BRAF activation in melanomas and other cancers. A number of BRAF fusions with different 5′ gene partners and BRAF exon breakpoints have been described, but the effects of different partners and breakpoints on cancer phenotypes and treatment responses has not been well characterized. Targeted RNA sequencing was used to screen 60 melanoma patient-derived xenograft (PDX) models for BRAF fusions. We identified three unique BRAF fusions, including a novel SEPT3-BRAF fusion, occurring in four tumors (4/60, 6.7%), all of which were “pan-negative” (lacking other common mutations) (4/18, 22.2%). The BRAF fusion PDX models showed variable growth rates and responses to MAPK inhibitors in vivo. Overexpression of BRAF fusions identified in our study, as well as other BRAF fusions previously identified in melanomas, resulted in a high degree of variability in 2D proliferation and 3D invasion between the different fusions. While exogenously expressed BRAF fusions all responded to MAPK inhibition in vitro, we observed potential differences in signaling and feedback mechanisms. In summary, BRAF fusions are actionable therapeutic targets, however there are significant differences in phenotypes, treatment responses, and signaling which may be clinically relevant.
Cervical squamous cell carcinoma-secreted exosomal miR-221-3p promotes lymphangiogenesis and lymphatic metastasis by targeting VASH1 Oncogene (IF 6.854) Pub Date : 2018-09-25 Chen-Fei Zhou, Jing Ma, Lei Huang, Hong-Yan Yi, Yan-Mei Zhang, Xiang-Guang Wu, Rui-Ming Yan, Li Liang, Mei Zhong, Yan-Hong Yu, Sha Wu, Wei Wang
Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.
Lysosomal acid ceramidase ASAH1 controls the transition between invasive and proliferative phenotype in melanoma cells Oncogene (IF 6.854) Pub Date : 2018-09-25 Justine Leclerc, David Garandeau, Charlotte Pandiani, Céline Gaudel, Karine Bille, Nicolas Nottet, Virginie Garcia, Pascal Colosetti, Sophie Pagnotta, Philippe Bahadoran, Garance Tondeur, Baharia Mograbi, Stéphane Dalle, Julie Caramel, Thierry Levade, Robert Ballotti, Nathalie Andrieu-Abadie, Corine Bertolotto
Phenotypic plasticity and subsequent generation of intratumoral heterogeneity underly key traits in malignant melanoma such as drug resistance and metastasis. Melanoma plasticity promotes a switch between proliferative and invasive phenotypes characterized by different transcriptional programs of which MITF is a critical regulator. Here, we show that the acid ceramidase ASAH1, which controls sphingolipid metabolism, acted as a rheostat of the phenotypic switch in melanoma cells. Low ASAH1 expression was associated with an invasive behavior mediated by activation of the integrin alphavbeta5-FAK signaling cascade. In line with that, human melanoma biopsies revealed heterogeneous staining of ASAH1 and low ASAH1 expression at the melanoma invasive front. We also identified ASAH1 as a new target of MITF, thereby involving MITF in the regulation of sphingolipid metabolism. Together, our findings provide new cues to the mechanisms underlying the phenotypic plasticity of melanoma cells and identify new anti-metastatic targets.
CHK2-mediated regulation of PARP1 in oxidative DNA damage response Oncogene (IF 6.854) Pub Date : 2018-09-25 Pei-Ching Hsu, Rajaneesh Karimpurath Gopinath, Yi-An Hsueh, Sheau-Yann Shieh
Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor, which upon activation, recruits downstream proteins by poly(ADP-ribosyl)ation (PARylation). However, it remains largely unclear how PARP1 activity is regulated. Interestingly, the data obtained through this study revealed that PARP1 was co-immunoprecipitated with checkpoint kinase 2 (CHK2), and the interaction was increased after oxidative DNA damage. Moreover, CHK2 depletion resulted in a reduction in overall PARylation. To further explore the functional relationship between PARP1 and CHK2, this study employed H2O2 to induce an oxidative DNA damage response in cells. Here, we showed that CHK2 and PARP1 interact in vitro and in vivo through the CHK2 SCD domain and the PARP1 BRCT domain. Furthermore, CHK2 stimulates the PARylation activity of PARP1 through CHK2-dependent phosphorylation. Consequently, the impaired repair associated with PARP1 depletion could be rescued by re-expression of wild-type PARP1 and the phospho-mimic but not the phospho-deficient mutant. Mechanistically, we showed that CHK2-dependent phosphorylation of PARP1 not only regulates its cellular localization but also promotes its catalytic activity and its interaction with XRCC1. These findings indicate that CHK2 exerts a multifaceted impact on PARP1 in response to oxidative stress to facilitate DNA repair and to maintain cell survival.
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