Artemisitene suppresses tumorigenesis by inducing DNA damage through deregulating c-Myc-topoisomerase pathway Oncogene (IF 7.519) Pub Date : 2018-05-24 Jian Chen, Wenjuan Li, Ke Cui, Kaiyuan Ji, Shuxiang Xu, Yang Xu
Cancer chemotherapeutic agents such as doxorubicin are DNA damage inducers that also kill normal cells, making them highly toxic to cancer patients. To improve the efficacy and safety of chemotherapy, it is important to develop new chemotherapeutic agents that selectively kill cancer cells. Here we demonstrate that artemisitene (ATT), a natural derivative of the antimalarial drug artemisinin, selectively induces DNA double-stranded breaks (DSBs) and apoptosis in various human cancer cells by suppressing the expression of topoisomerases in human cancer cells. ATT effectively kills human cancer cells without apparent cytotoxicity on normal human cells or mouse liver and kidney. We discovered that c-Myc induces the expression of topoisomerases to prevent accumulation of DNA damage in human cancer cells. ATT selectively destabilizes c-Myc in human cancer cells by promoting the ubiquitination of c-Myc through the specific induction of the c-Myc E3 ligase NEDD4. Therefore, ATT represents a promising new chemotherapeutic drug candidate that can eliminate human cancer cells with minimized cytotoxic effects on normal cells.
Myeloid-restricted ablation of Shp2 restrains melanoma growth by amplifying the reciprocal promotion of CXCL9 and IFN-γ production in tumor microenvironment Oncogene (IF 7.519) Pub Date : 2018-05-24 P. Xiao, Y. Guo, H. Zhang, X. Zhang, H. Cheng, Q. Cao, Y. Ke
The Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp2) is generally considered to be an oncogene owing to its ability in enhancing the malignancy of multiple types of tumor cells; however, its role in modulating tumor immunity remains largely elusive. Here, we reported that myeloid-restricted ablation of Shp2 suppressed melanoma growth. Mechanistically, loss of Shp2 potentiates macrophage production of CXCL9 in response to IFN-γ and tumor cell-derived cytokines, thereby facilitating the tumor infiltration of IFN-γ-producing T cells that could in turn support CXCL9 production within tumor microenvironment. Collectively, our findings highlight a causative role of myeloid Shp2 in dampening T cell-mediated antitumor immunity by restraining the macrophage/CXCL9-T cell/IFN-γ feedback loop. Thus, targeting macrophage Shp2 may help to create a Th1-dominant tumor immune microenvironment.
Molecular alterations of cancer cell and tumour microenvironment in metastatic gastric cancer Oncogene (IF 7.519) Pub Date : 2018-05-23 Weilin Li, Jennifer Mun-Kar Ng, Chi Chun Wong, Enders Kwok Wai Ng, Jun Yu
The term metastasis is widely used to describe the endpoint of the process by which tumour cells spread from the primary location to an anatomically distant site. Achieving successful dissemination is dependent not only on the molecular alterations of the cancer cells themselves, but also on the microenvironment through which they encounter. Here, we reviewed the molecular alterations of metastatic gastric cancer (GC) as it reflects a large proportion of GC patients currently seen in clinic. We hope that further exploration and understanding of the multistep metastatic cascade will yield novel therapeutic targets that will lead to better patient outcomes.
Integration of Ca2+ signaling regulates the breast tumor cell response to simvastatin and doxorubicin Oncogene (IF 7.519) Pub Date : 2018-05-23 Souleymane Abdoul-Azize, Catherine Buquet, Hong Li, Jean-Michel Picquenot, Jean-Pierre Vannier
Recent studies have suggested that the lipid-lowering agent simvastatin holds great promise as a cancer therapeutic; it inhibits the growth of multiple tumors, including triple-negative breast cancer. Doxorubicin- and simvastatin-induced cytotoxicity has been associated with the modulation of Ca2+ signaling, but the underlying mechanisms remain incompletely understood. Here we identify how Ca2+ signaling regulates the breast tumor cell response to doxorubicin and simvastatin. These two drugs inhibit cell survival while increasing apoptosis in two human breast cancer cell lines and five primary breast tumor specimens through the modulation of Ca2+ signaling. Signal transduction and functional studies revealed that both simvastatin and doxorubicin trigger persistent cytosolic Ca2+ release, thereby stimulating the proapoptotic BIM pathway and mitochondrial Ca2+ overload, which are responsible for metabolic dysfunction and apoptosis induction. Simvastatin and doxorubicin suppress the prosurvival ERK1/2 pathway in a Ca2+-independent and Ca2+-dependent manner, respectively. In addition, reduction of the Ca2+ signal by chelation or pharmacological inhibition significantly prevents drug-mediated anticancer signaling. Unexpectedly, a scratch-wound assay indicated that these two drugs induce rapid cell migration, while inhibiting cell invasion and colony formation in a Ca2+-dependent manner. Further, the in vivo data for MDA-MB-231 xenografts demonstrate that upon chelation of Ca2+, the ability of both drugs to reduce the tumor burden was significantly reduced via caspase-3 deactivation. Our results establish a calcium-based mechanism as crucial for executing the cell death process triggered by simvastatin and doxorubicin, and suggest that combining simvastatin with doxorubicin may be an effective regimen for the treatment of breast cancer.
K6 linked polyubiquitylation of FADD by CHIP prevents death inducing signaling complex formation suppressing cell death Oncogene (IF 7.519) Pub Date : 2018-05-23 Jinho Seo, Eun-Woo Lee, Jihye Shin, Daehyeon Seong, Young Woo Nam, Manhyung Jeong, Seon-Hyeong Lee, Cheolju Lee, Jaewhan Song
Fas-associated death domain (FADD) is an adaptor protein recruiting complexes of caspase 8 to death ligand receptors to induce extrinsic apoptotic cell death in response to a TNF superfamily member. Although, formation of the complex of FADD and caspase 8 upon death stimuli has been studied in detail, posttranslational modifications fine-tuning these processes have yet to be identified. Here we revealed that K6-linked polyubiquitylation of FADD on lysines 149 and 153 mediated by C terminus HSC70-interacting protein (CHIP) plays an important role in preventing formation of the death inducing signaling complex (DISC), thus leading to the suppression of cell death. Cells depleted of CHIP showed higher sensitivity toward death ligands such as FasL and TRAIL, leading to upregulation of DISC formation composed of a death receptor, FADD, and caspase 8. CHIP was able to bind to FADD, induce K6-linked polyubiquitylation of FADD, and suppress DISC formation. By mass spectrometry, lysines 149 and 153 of FADD were found to be responsible for CHIP-mediated FADD ubiquitylation. FADD mutated at these sites was capable of more potent cell death induction as compared with the wild type and was no longer suppressed by CHIP. On the other hand, CHIP deficient in E3 ligase activity was not capable of suppressing FADD function and of FADD ubiquitylation. CHIP depletion in ME-180 cells induced significant sensitization of these cells toward TRAIL in xenograft analyses. These results imply that K6-linked ubiquitylation of FADD by CHIP is a crucial checkpoint in cytokine-dependent extrinsic apoptosis.
Upregulation of the long noncoding RNA FOXD2-AS1 promotes carcinogenesis by epigenetically silencing EphB3 through EZH2 and LSD1, and predicts poor prognosis in gastric cancer Oncogene (IF 7.519) Pub Date : 2018-05-23 Tong-peng Xu, Wen-yu Wang, Pei Ma, You Shuai, Kun Zhao, Yan-fen Wang, Wei Li, Rui Xia, Wen-ming Chen, Er-bao Zhang, Yong-qian Shu
Accumulating data indicate that long noncoding RNAs (lncRNAs) serve as important modulators in biological processes and are dysregulated in diverse tumors. The function of FOXD2-AS1 in gastric cancer (GC) progression and related biological mechanisms remain undefined. A comprehensive analysis identified that FOXD2-AS1 enrichment was upregulated markedly in GC and positively correlated with a large tumor size, a later pathologic stage, and a poor prognosis. Gene-set enrichment analysis (GSEA) in GEO datasets uncovered that cell cycle and DNA replication associated genes were enriched in patients with high FOXD2-AS1 expression. Loss of FOXD2-AS1 function inhibited cell growth via inhibiting the cell cycle in GC, whereas upregulation of FOXD2-AS1 expression promoted cancer progression. The enhancer of zeste homolog 2 (EZH2) and lysine (K)-specific demethylase 1A (LSD1) proteins were found to serve as binding partners of FOXD2-AS1 and mediators of FOXD2-AS1 function. Mechanically, FOXD2-AS1 promoted GC tumorigenesis partly through EZH2 and LSD1 mediated EphB3 downregulation. The present results revealed that FOXD2-AS1 acted as a tumor inducer in GC partly through EphB3 inhibition by direct interaction with EZH2 and LSD1, and may prove to be a potential biomarker of carcinogenesis.
Estrogen receptor β promotes renal cell carcinoma progression via regulating LncRNA HOTAIR-miR-138/200c/204/217 associated CeRNA network Oncogene (IF 7.519) Pub Date : 2018-05-23 Jie Ding, Chiuan-Ren Yeh, Yin Sun, Changyi Lin, Joshua Chou, Zhenyu Ou, Chawnshang Chang, Jun Qi, Shuyuan Yeh
Recent studies indicated that the estrogen receptor beta (ERβ) could affect the progression of prostate and bladder tumors, however, its roles in the renal cell carcinoma (RCC), remain to be elucidated. Here, we provide clinical evidence that ERβ expression is correlated in a negative manner with the overall survival/disease-free survival in RCC patients. Mechanism dissection revealed that targeting ERβ with ERβ-shRNA and stimulating the transactivation of ERβ with 17β-estradiol or environmental endocrine disrupting chemicals, all resulted in altering the lncRNA HOTAIR expression. The ERβ-modulated HOTAIR is able to function via antagonizing several microRNAs, including miR-138, miR-200c, miR-204, or miR-217 to impact various oncogenes, including ADAM9, CCND2, EZH2, VEGFA, VIM, ZEB1, and ZEB2, to promote RCC proliferation and invasion. Together, the identification of the ERβ-HOTAIR axis may provide us new biomarkers and/or therapeutic targets to better suppress RCC progression in the future.
Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis Oncogene (IF 7.519) Pub Date : 2018-05-23 Susanne Vorhagen, Dominik Kleefisch, Oana-Diana Persa, Annika Graband, Alexandra Schwickert, Michael Saynisch, Michael Leitges, Carien M. Niessen, Sandra Iden
The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKCλ function as a complex to promote tumorigenesis. Molecularly, Par3/aPKCλ cooperate to promote Akt, ERK and NF-κB signaling during tumor initiation to sustain growth, whereas aPKCλ dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKCλ cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKCλ and Par3 promote a tumor-permissive environment. Importantly, aPKCλ also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKCλ cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.
PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence Oncogene (IF 7.519) Pub Date : 2018-05-23 Mary E. Klein, Mark A. Dickson, Cristina Antonescu, Li-Xuan Qin, Scott J. Dooley, Afsar Barlas, Katia Manova, Gary K. Schwartz, Aimee M. Crago, Samuel Singer, Andrew Koff, William D. Tap
CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.
xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression Oncogene (IF 7.519) Pub Date : 2018-05-23 Xiangming Ji, Jun Qian, S. M. Jamshedur Rahman, Peter J. Siska, Yong Zou, Bradford K. Harris, Megan D. Hoeksema, Irina A. Trenary, Chen Heidi, Rosana Eisenberg, Jeffrey C. Rathmell, Jamey D. Young, Pierre P. Massion
Many tumors increase uptake and dependence on glucose, cystine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer research. Recent studies demonstrated that smoking could induce the expression of xCT (SLC7A11) in oral cancer cells, suggesting that overexpression of xCT may support lung tumor progression. We hypothesized that overexpression of xCT occurs in lung cancer cells to satisfy the metabolic requirements for growth and survival. Our results demonstrated that 1) xCT was highly expressed at the cytoplasmic membrane in non-small cell lung cancer (NSCLC), 2) the expression of xCT was correlated with advanced stage and predicted a worse 5-year survival, 3) targeting xCT transport activity in xCT overexpressing NSCLC cells with sulfasalazine decreased cell proliferation and invasion in vitro and in vivo and 4) increased dependence on glutamine was observed in xCT overexpressed normal airway epithelial cells. These results suggested that xCT regulate metabolic requirements during lung cancer progression and be a potential therapeutic target in NSCLC.
Multicellular detachment generates metastatic spheroids during intra-abdominal dissemination in epithelial ovarian cancer Oncogene (IF 7.519) Pub Date : 2018-05-23 Sara Al Habyan, Christina Kalos, Joseph Szymborski, Luke McCaffrey
Ovarian cancer is the most lethal gynecological cancer, where survival rates have had modest improvement over the last 30 years. Metastasis of cancer cells is a major clinical problem, and patient mortality occurs when ovarian cancer cells spread beyond the confinement of ovaries. Disseminated ovarian cancer cells typically spread within the abdomen, where ascites accumulation aids in their transit. Metastatic ascites contain multicellular spheroids, which promote chemo-resistance and recurrence. However, little is known about the origin and mechanisms through which spheroids arise. Using live-imaging of 3D culture models and animal models, we report that epithelial ovarian cancer (EOC) cells, the most common type of ovarian cancer, can spontaneously detach as either single cells or clusters. We report that clusters are more resistant to anoikis and have a potent survival advantage over single cells. Using in vivo lineage tracing, we found that multicellular spheroids arise preferentially from collective detachment, rather than aggregation in the abdomen. Finally, we report that multicellular spheroids from collective detachment are capable of seeding intra-abdominal metastases that retain intra-tumoral heterogeneity from the primary tumor.
Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation Oncogene (IF 7.519) Pub Date : 2018-05-22 Julien Boetto, Caroline Apra, Franck Bielle, Matthieu Peyre, Michel Kalamarides
Somatic activating mutations of smoothened (SMO), a component of the embryonic sonic hedgehog (SHH) signaling pathway, are found in 3–5% of grade I meningiomas, most of them corresponding to meningothelial meningiomas located at the anterior skull base. By generating different developmental stage-specific conditional activations in mice, we define a restricted developmental window during which conditional activation of Smo in Prostaglandin D2-synthase-positive mesoderm-derived meningeal layer of the skull base results in meningothelial meningioma formation. We show a selective vulnerability of the arachnoid from the skull base to Smo activation to initiate tumor development. This prenatal period and specific topography are correlated to the timing and location of SHH signaling involvement in the formation of craniofacial and meninges patterning, strongly corroborating the hypothesis of a developmental origin for Smo-activated meningiomas. Finally, we provide preclinical in vitro evidence of the efficacy of the SMO-inhibitor Sonidegib, supporting further preclinical and clinical evaluation of targeted treatment for refractory SMO-mutant meningiomas.
Tumor-derived exosomes promote tumor self-seeding in hepatocellular carcinoma by transferring miRNA-25-5p to enhance cell motility Oncogene (IF 7.519) Pub Date : 2018-05-22 Hao Liu, Wei Chen, Xiao Zhi, En-Jiang Chen, Tao Wei, Jian Zhang, Jian Shen, Li-Qiang Hu, Bin Zhao, Xin-Hua Feng, Xue-Li Bai, Ting-Bo Liang
Tumor self-seeding occurs when circulating malignant cells reinfiltrate the original tumor. The process may breed more aggressive tumor cells, which may contribute to cancer progression. In this study, we observed tumor self-seeding in mouse xenograft models of hepatocellular carcinoma (HCC) for the first time. We confirmed that circulating tumor cell uptake of tumor-derived exosomes, which are increasingly recognized as key instigators of cancer progression by facilitating cell–cell communication, promoted tumor self-seeding by enhancing the invasive and migration capability of recipient HCC cells. Horizontal transfer of exosomal microRNA-25-5p to anoikis-resistant HCC cells significantly enhanced their migratory and invasive abilities, whereas inhibiting microRNA-25-5p alleviated these effects. Our experiments delineate an exosome-based novel pathway employed by functional microRNA from the original tumor cells that can influence the biological fate of circulating tumor cells.
Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy Oncogene (IF 7.519) Pub Date : 2018-05-22 Bo Zhu, Liming Tang, Shuyang Chen, Chengqian Yin, Shiguang Peng, Xin Li, Tongzheng Liu, Wei Liu, Changpeng Han, Lukasz Stawski, Zhi-Xiang Xu, Guangbiao Zhou, Xiang Chen, Xiumei Gao, Colin R. Goding, Nan Xu, Rutao Cui, Peng Cao
Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited. Here we provide biochemical evidence demonstrating that ultraviolet radiation (UVR) induction of PD-L1 in skin is directly controlled by nuclear factor E2-related transcription factor 2 (NRF2). Depletion of NRF2 significantly induces tumor infiltration by both CD8+ and CD4+ T cells to suppress melanoma progression, and combining NRF2 inhibition with anti-PD-1 treatment enhanced its anti-tumor function. Our studies identify a critical and targetable PD-L1 upstream regulator and provide an alternative strategy to inhibit the PD-1/PD-L1 signaling in melanoma treatment.
LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy Oncogene (IF 7.519) Pub Date : 2018-05-21 Leonie Rossow, Simona Veitl, Sandra Vorlová, Jacqueline K. Wax, Anja E. Kuhn, Verena Maltzahn, Berin Upcin, Franziska Karl, Helene Hoffmann, Sabine Gätzner, Matthias Kallius, Rajender Nandigama, Daniela Scheld, Ster Irmak, Sabine Herterich, Alma Zernecke, Süleyman Ergün, Erik Henke
The potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.
E-cadherin in contact inhibition and cancer Oncogene (IF 7.519) Pub Date : 2018-05-21 Alisha M. Mendonsa, Tae-Young Na, Barry M. Gumbiner
E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding between cells is important in mediating contact inhibition of proliferation when cells reach confluence. Loss of E-cadherin expression results in loss of contact inhibition and is associated with increased cell motility and advanced stages of cancer. In this review we discuss the role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer.
Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer Oncogene (IF 7.519) Pub Date : 2018-05-21 Anne Serrao, Laura M. Jenkins, Alexander A. Chumanevich, Ben Horst, Jiaxin Liang, Michael L. Gatza, Nam Y. Lee, Igor B. Roninson, Eugenia V. Broude, Karthikeyan Mythreye
CDK8 is a transcription-regulating kinase that controls TGF-β/BMP-responsive SMAD transcriptional activation and turnover through YAP1 recruitment. However, how the CDK8/YAP1 pathway influences SMAD1 response in cancer remains unclear. Here we report that SMAD1-driven epithelial-to-mesenchymal transition (EMT) is critically dependent on matrix rigidity and YAP1 in a wide spectrum of cancer models. We find that both genetic and pharmacological inhibition of CDK8 and its homologous twin kinase CDK19 leads to abrogation of BMP-induced EMT. Notably, selectively blocking CDK8/19 specifically abrogates tumor cell invasion, changes in EMT-associated transcription factors, E-cadherin expression and YAP nuclear localization both in vitro and in vivo in a murine syngeneic EMT model. Furthermore, RNA-seq meta-analysis reveals a direct correlation between CDK8 and EMT-associated transcription factors in patients. Our findings demonstrate that CDK8, an emerging therapeutic target, coordinates growth factor and mechanical cues during EMT and invasion.
NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression Oncogene (IF 7.519) Pub Date : 2018-05-21 Sheng Tan, Hua Li, Weijie Zhang, Yunying Shao, Yuan Liu, Haiyang Guan, Jun Wu, Yani Kang, Junsong Zhao, Qing Yu, Yunzhao Gu, Keshuo Ding, Min Zhang, Wenchang Qian, Yong Zhu, Huayong Cai, Changyu Chen, Peter E. Lobie, Xiaodong Zhao, Jielin Sun, Tao Zhu
Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3′RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3′UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3′ UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.
Circadian regulator NR1D2 regulates glioblastoma cell proliferation and motility Oncogene (IF 7.519) Pub Date : 2018-05-18 Min Yu, Wenjing Li, Qianqian Wang, Yan Wang, Fei Lu
Nuclear receptor NR1D2 is originally characterized as the repressor of genes involved in circadian rhythm. Recently, it is documented that NR1D2 is overexpressed in various cancers. However, the pathways and biological functions that NR1D2 involved in cancers remain poorly understood. Here, we reported that NR1D2 was abundant in human glioblastoma (GBM) tissue and cell lines but not primary human astrocytes. Silencing of NR1D2 changed the morphology of GBM cells, inhibited cell proliferation and motility, whereas had no effects on apoptosis. Importantly, based on RNA-seq and ChIP assay, we identified receptor tyrosine kinase AXL as a new transcriptional target of NR1D2 in GBM cells. AXL mediated partially the regulatory effects of NR1D2 on PI3K/AKT axis and promoted proliferation, migration, and invasion of GBM cells. Besides, NR1D2 knockdown remarkably impaired the maturation of focal adhesion and assembly of F-actin, along with downregulated p-FAK, and proteins involved in actin nucleation and polymerization (p-Rac1/Cdc42, WAVE and PFN2). Moreover, NR1D2 had more targets other than AXL to regulate epithelial-to-mesenchymal transition and cell motility in GBM cells. Altogether, our findings uncover a GBM-promoting role of NR1D2 and provide the rationale for targeting NR1D2 as a potential therapeutic approach.
NEDD9 promotes oncogenic signaling, a stem/mesenchymal gene signature, and aggressive ovarian cancer growth in mice Oncogene (IF 7.519) Pub Date : 2018-05-18 Rashid Gabbasov, Fang Xiao, Caitlin G. Howe, Laura E. Bickel, Shane W. O’Brien, Daniel Benrubi, Thuy-Vy Do, Yan Zhou, Emmanuelle Nicolas, Kathy Q. Cai, Samuel Litwin, Sachiko Seo, Erica A. Golemis, Denise C. Connolly
Neural precursor cell expressed, developmentally downregulated 9 (NEDD9) supports oncogenic signaling in a number of solid and hematologic tumors. Little is known about the role of NEDD9 in ovarian carcinoma (OC), but available data suggest elevated mRNA and protein expression in advanced stage high-grade cancers. We used a transgenic MISIIR-TAg mouse OC model combined with genetic ablation of Nedd9 to investigate its action in the development and progression of OC. A Nedd9−/− genotype delayed tumor growth rate, reduced incidence of ascites, and reduced expression and activation of signaling proteins including SRC, STAT3, E-cadherin, and AURKA. Cell lines established from MISIIR-TAg;Nedd9−/− and MISIIR-TAg;Nedd9+/+ mice exhibited altered migration and invasion. Growth of these cells in a syngeneic allograft model indicated that systemic Nedd9 loss in the microenvironment had little impact on tumor allograft growth, but in a Nedd9 wild-type background Nedd9−/− allografts exhibited significantly reduced growth, dissemination, and oncogenic signaling compared to Nedd9+/+ allografts. Gene expression analysis revealed that Nedd9+/+ tumors exhibited more mesenchymal “stem-like” transcriptional program, including increased expression of Aldh1a1 and Aldh1a2. Conversely, loss of Nedd9 resulted in increased expression of differentiation genes, including fallopian tube markers Foxj1, Ovgp1, and Pax8. Collectively, these data suggest that tumor cell-intrinsic Nedd9 expression promotes OC development and progression by broad induction of oncogenic protein signaling and stem/mesenchymal gene expression.
Ets-1 promoter-associated noncoding RNA regulates the NONO/ERG/Ets-1 axis to drive gastric cancer progression Oncogene (IF 7.519) Pub Date : 2018-05-18 Dan Li, Yajun Chen, Hong Mei, Wanju Jiao, Huajie Song, Lin Ye, Erhu Fang, Xiaojing Wang, Feng Yang, Kai Huang, Liduan Zheng, Qiangsong Tong
Emerging studies have indicated the essential functions of long noncoding RNAs (lncRNAs) during cancer progression. However, whether lncRNAs contribute to the upregulation of v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), an established oncogenic protein facilitating tumor invasion and metastasis, in gastric cancer remains elusive. Herein, we identified Ets-1 promoter-associated noncoding RNA (pancEts-1) as a novel lncRNA associated with the gastric cancer progression via mining of publicly available datasets and rapid amplification of cDNA ends. RNA pull-down, RNA immunoprecipitation, in vitro binding, and RNA electrophoretic mobility shift assays indicated the binding of pancEts-1 to non-POU domain containing octamer binding (NONO) protein. Mechanistically, pancEts-1 facilitated the physical interaction between NONO and Ets related gene (ERG), resulting in increased ERG transactivation and transcription of Ets-1 associated with gastric cancer progression. In addition, pancEts-1 facilitated the growth and aggressiveness of gastric cancer cells via interacting with NONO. In gastric cancer tissues, pancEts-1, NONO, and ERG were upregulated and significantly correlated with Ets-1 levels. High levels of pancEts-1, NONO, ERG, or Ets-1 were respectively associated with poor survival of gastric cancer patients, whereas simultaneous expression of all of them (HR = 3.012, P = 0.105) was not an independent prognostic factor for predicting clinical outcome. Overall, these results demonstrate that lncRNA pancEts-1 exhibits oncogenic properties that drive the progression of gastric cancer via regulating the NONO/ERG/Ets-1 axis.
C5a induces A549 cell proliferation of non-small cell lung cancer via GDF15 gene activation mediated by GCN5-dependent KLF5 acetylation Oncogene (IF 7.519) Pub Date : 2018-05-18 Chenhui Zhao, Yongting Li, Wen Qiu, Fengxia He, Weiming Zhang, Dan Zhao, Zhiwei Zhang, Erbao Zhang, Pei Ma, Yiqian Liu, Ling Ma, Fengming Yang, Yingwei Wang, Yongqian Shu
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and multiple evidence has confirmed that C5a production is elevated in NSCLC microenvironment. Although NSCLC cell proliferation induced by C5a has been reported, the involved mechanism has not been elucidated. In this study, we examined the proliferation-related genes (i.e., KLF5, GCN5, and GDF15) and C5a receptor (C5aR) expression in tumor tissues as well as C5a concentration in plasma of NSCLC patients, and then determined the roles of KLF5, GCN5, and GDF15 in C5a-triggered NSCLC cell proliferation and the related mechanism both in vitro and in vivo. Our results found that the expression of KLF5, GCN5, GDF15, C5aR, and C5a was significantly upregulated in NSCLC patients. Mechanistic exploration in vitro revealed that C5a could facilitate A549 cell proliferation through increasing KLF5, GCN5, and GDF15 expression. Besides, KLF5 and GCN5 could form a complex, binding to GDF15 promoter in a KLF5-dependent manner and leading to GDF15 gene transcription. More importantly, GCN5-mediated KLF5 acetylation contributing to GDF15 gene transcription and cell proliferation upon C5a stimulation, the region (−103 to +58 nt) of GDF15 promoter which KLF5 could bind to, and two new KLF5 lysine sites (K335 and K391) acetylated by GCN5 were identified for the first time. Furthermore, our experiment in vivo demonstrated that the growth of xenograft tumors in BALB/c nude mice was greatly suppressed by the silence of KLF5, GCN5, or GDF15. Collectively, these findings disclose that C5a-driven KLF5–GCN5–GDF15 axis had a critical role in NSCLC proliferation and might serve as targets for NSCLC therapy.
A new method of identifying glioblastoma subtypes and creation of corresponding animal models Oncogene (IF 7.519) Pub Date : 2018-05-17 Xia Zhou, Gonghua Li, Sanqi An, Wen-Xing Li, Huihui Yang, Yicheng Guo, Zhi Dai, Shaoxing Dai, Junjuan Zheng, Jingfei Huang, Antonio Iavarone, Xudong Zhao
Glioblastoma (GBM) accounts for up to 50% of brain parenchymal tumors. It is the most malignant type of brain cancer with very poor survival and limited remedies. Cancer subtyping is important for cancer research and therapy. Here, we report a new subtyping method for GBM based on the genetic alterations of CDKN2A and TP53 genes. CDKN2A and TP53 are the most frequently mutated genes with mutation rates of 60 and 30%, respectively. We found that patients with deletion of CDKN2A possess worse survival than those with TP53 mutation. Interestingly, survival of patients with both TP53 mutation and CDKN2A deletion is no worse than for those with only one of these genetic alterations, but similar to those with TP53 mutation alone. Next, we investigated differences in the gene expression profile between TP53 and CDKN2A samples. Consistent with the survival data, the samples with both TP53 mutation and CDKN2A deletion showed a gene expression profile similar to those samples with TP53 mutation alone. Finally, we found that activation of RAS pathway plus Cdkn2a/b silencing can induce GBM, in a similar way to tumor induction by RAS activation plus TP53 silencing. In conclusion, we show that the genetic alterations of CDKN2A and TP53 may be used to stratify GBM, and the new animal models matching this stratification method were generated.
Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer Oncogene (IF 7.519) Pub Date : 2018-05-17 Miran Rada, Sameera Nallanthighal, Jennifer Cha, Kerry Ryan, Jessica Sage, Catherine Eldred, Maria Ullo, Sandra Orsulic, Dong-Joo Cheon
Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells. Mechanistically, we show that COL11A1 activates Src-PI3K/Akt-NF-kB signaling to induce the expression of three inhibitor apoptosis proteins (IAPs), including XIAP, BIRC2, and BIRC3. Genetic and pharmacological inhibition of XIAP, BIRC2, and BIRC3 is sufficient to restore cisplatin-induced apoptosis in ovarian cancer cells in the presence of COL11A1 in ovarian cancer cells and xenograft mouse models, respectively. We also show that the components of COL11A1- integrin α1β1/DDR2- Src-PI3K/Akt-NF-kB-IAP signaling pathway serve as poor prognosis markers in ovarian cancer patients. Taken together, our results suggest novel mechanisms by which COL11A1 confers cisplatin resistance in ovarian cancer. Our study also uncovers IAPs as promising therapeutic targets to reduce cisplatin resistance in ovarian cancer, particularly in recurrent ovarian cancer expressing high levels of COL11A1.
Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations Oncogene (IF 7.519) Pub Date : 2018-05-16 Ioannis Zerdes, Alexios Matikas, Jonas Bergh, George Z. Rassidakis, Theodoros Foukakis
The programmed death protein 1 (PD-1) and its ligand (PD-L1) represent a well-characterized immune checkpoint in cancer, effectively targeted by monoclonal antibodies that are approved for routine clinical use. The regulation of PD-L1 expression is complex, varies between different tumor types and occurs at the genetic, transcriptional and post-transcriptional levels. Copy number alterations of PD-L1 locus have been reported with varying frequency in several tumor types. At the transcriptional level, a number of transcriptional factors seem to regulate PD-L1 expression including HIF-1, STAT3, NF-κΒ, and AP-1. Activation of common oncogenic pathways such as JAK/STAT, RAS/ERK, or PI3K/AKT/MTOR, as well as treatment with cytotoxic agents have also been shown to affect tumoral PD-L1 expression. Correlative studies of clinical trials with PD-1/PD-L1 inhibitors have so far shown markedly discordant results regarding the value of PD-L1 expression as a marker of response to treatment. As the indications for immune checkpoint inhibition broaden, understanding the regulation of PD-L1 in cancer will be of utmost importance for defining its role as predictive marker but also for optimizing strategies for cancer immunotherapy. Here, we review the current knowledge of PD-L1 regulation, and its use as biomarker and as therapeutic target in cancer.
The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation Oncogene (IF 7.519) Pub Date : 2018-05-16 Maria Polycarpou-Schwarz, Matthias Groß, Pieter Mestdagh, Johanna Schott, Stefanie E. Grund, Catherina Hildenbrand, Joachim Rom, Sebastian Aulmann, Hans-Peter Sinn, Jo Vandesompele, Sven Diederichs
Breast cancer is a leading cause of cancer-related death in women. Small open reading frame (sORF)-encoded proteins or microproteins constitute a new class of molecules often transcribed from presumed long non-coding RNA transcripts (lncRNAs). The translation of some of these sORFs has been confirmed, but their cellular function and importance remains largely unknown. Here, we report the identification and characterization of a novel microprotein of 10 kDa, which we named Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1). CASIMO1 RNA is overexpressed predominantly in hormone receptor-positive breast tumors. Its knockdown leads to decreased proliferation in multiple breast cancer cell lines. Its loss disturbs the organization of the actin cytoskeleton, leads to inhibition of cell motility, and causes a G0/G1 cell cycle arrest. The proliferation phenotype upon overexpression is observed only with CASIMO1 protein expression, but not with a non-translatable mutant attributing the effects to the sORF-derived protein rather than a lncRNA function. CASIMO1 microprotein interacts with squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis and a known oncogene in breast cancer. Overexpression of CASIMO1 leads to SQLE protein accumulation without affecting its RNA levels and increased lipid droplet clustering, while knockdown of CASIMO1 decreased SQLE protein abundance and ERK phosphorylation downstream of SQLE. Importantly, SQLE knockdown mimicked the CASIMO1 knockdown phenotype and in turn SQLE overexpression fully rescued the effect of CASIMO1 knockdown. These findings establish CASIMO1 as the first functional microprotein that plays a role in carcinogenesis and is implicated in the cell lipid homeostasis.
COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer Oncogene (IF 7.519) Pub Date : 2018-05-16 Rachana Garg, Jorge M. Blando, Carlos J. Perez, Priti Lal, Michael D. Feldman, Emer M. Smyth, Emanuela Ricciotti, Tilo Grosser, Fernando Benavides, Marcelo G. Kazanietz
The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE2 production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.
LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling Oncogene (IF 7.519) Pub Date : 2018-05-15 Jianming Tang, Yanxin Li, Youzhou Sang, Bo Yu, Deguan Lv, Weiwei Zhang, Haizhong Feng
Recent molecularly targeted approach gains advance in breast cancer treatment. However, the estimated 5-year survival rate has not met the desired expectation for improvement, especially for patients with triple-negative breast cancer (TNBC). Here we report that the lncRNA PVT1 promotes KLF5/beta-catenin signaling to drive TNBC tumorigenesis. PVT1 is upregulated in clinical TNBC tumors. Using genetic approaches targeting PVT1 in TNBC cells, we found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistically, PVT1 binds with KLF5 and increases its stability via BAP1, which upregulates beta-catenin signaling, resulting in enhanced TNBC tumorigenesis. PVT1, KLF5, and beta-catenin were also revealed to be co-expressed in clinical TNBC samples. Our findings uncover a new singaling pathway to mediate TNBC, and provide PVT1 as a new target for improving treatment of TNBC.
ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors Oncogene (IF 7.519) Pub Date : 2018-05-15 Katrien Berns, Joseph J. Caumanns, E. Marielle Hijmans, Annemiek M. C. Gennissen, Tesa M. Severson, Bastiaan Evers, G. Bea A. Wisman, Gert Jan Meersma, Cor Lieftink, Roderick L. Beijersbergen, Hiroaki Itamochi, Ate G. J. van der Zee, Steven de Jong, René Bernards
Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells. Importantly, small molecule inhibitors of the BET (bromodomain and extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1A mutated cell lines, both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1A mutated ovarian clear cell carcinomas.
Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12 Oncogene (IF 7.519) Pub Date : 2018-05-14 Urszula L. McClurg, Nay C. T. H. Chit, Mahsa Azizyan, Joanne Edwards, Arash Nabbi, Karl T. Riabowol, Sirintra Nakjang, Stuart R. McCracken, Craig N. Robson
The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not completely defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer. Our findings explain why USP12 is one of the 12 most commonly overexpressed cancer-associated genes located near an amplified super-enhancer. We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer. Consequently, USP12 levels are predictive not only of cancer development but also of patient’s therapy resistance, relapse and survival. Therefore, our findings suggest that USP12 could serve as a promising therapeutic target in currently incurable castrate-resistant prostate cancer.
NRP-1 interacts with GIPC1 and α6/β4-integrins to increase YAP1/∆Np63α-dependent epidermal cancer stem cell survival Oncogene (IF 7.519) Pub Date : 2018-05-14 Daniel Grun, Gautam Adhikary, Richard L. Eckert
We have identified an epidermal cancer stem (ECS) cell population that drives formation of rapidly growing and highly invasive and vascularized tumors. VEGF-A and neuropilin-1 (NRP-1) are highly expressed in ECS cell tumors and VEGF-A/NRP-1 interaction is required for ECS cell survival and tumor vascularization. We now identify a novel signaling cascade that is triggered by VEGF-A/NRP-1. We show that NRP-1 forms a complex with GIPC1 and α6/β4-integrin to activate FAK/Src signaling, which leads to stabilization of a YAP1/∆Np63α to enhance ECS cell survival, invasion, and angiogenesis. Loss of NRP-1, GIPC1, α6/β4-integrins, YAP1, or ∆Np63α reduces these responses. Moreover, restoration of constituently active YAP1 or ∆Np63α in NRP-1 null cells restores the ECS cell phenotype. Tumor xenograft experiments show that NRP-1 knockout ECS cells form small tumors characterized by reduced vascularization as compared to wild-type cells. The NRP-1 knockout tumors display signaling changes consistent with a role for the proposed signaling cascade. These studies suggest that VEGF-A interacts with NRP-1 and GIPC1 to regulate α6/β4-integrin, FAK, Src, PI3K/PDK1, LATS1 signaling to increase YAP1/∆Np63α accumulation to drive ECS cell survival, angiogenesis, and tumor formation.
A novel long non-coding RNA linc-ZNF469-3 promotes lung metastasis through miR-574-5p-ZEB1 axis in triple negative breast cancer Oncogene (IF 7.519) Pub Date : 2018-05-14 Po-Shun Wang, Cheng-Han Chou, Cheng-Han Lin, Yun-Chin Yao, Hui-Chuan Cheng, Hao-Yi Li, Yu-Chung Chuang, Chia-Ning Yang, Luo-Ping Ger, Yu-Chia Chen, Forn-Chia Lin, Tang-Long Shen, Michael Hsiao, Pei-Jung Lu
Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients.
Circulating-free tumour DNA and the promise of disease phenotyping in hepatocellular carcinoma Oncogene (IF 7.519) Pub Date : 2018-05-14 David J. Pinato
Circulating-free tumour DNA and the promise of disease phenotyping in hepatocellular carcinoma Circulating-free tumour DNA and the promise of disease phenotyping in hepatocellular carcinoma, Published online: 14 May 2018; doi:10.1038/s41388-018-0262-8 Circulating-free tumour DNA and the promise of disease phenotyping in hepatocellular carcinoma
Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer Oncogene (IF 7.519) Pub Date : 2018-05-14 Kyle Knickelbein, Jingshan Tong, Dongshi Chen, Yi-Jun Wang, Sandra Misale, Alberto Bardelli, Jian Yu, Lin Zhang
Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function Oncogene (IF 7.519) Pub Date : 2018-05-14 Kinisha Gala, Qing Li, Amit Sinha, Pedram Razavi, Madeline Dorso, Francisco Sanchez-Vega, Young Rock Chung, Ronald Hendrickson, James Hsieh, Michael Berger, Nikolaus Schultz, Alessandro Pastore, Omar Abdel-Wahab, Sarat Chandarlapaty
Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.
Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets Oncogene (IF 7.519) Pub Date : 2018-05-11 Leah A. Gates, Guowei Gu, Yue Chen, Aarti D. Rohira, Jonathan T. Lei, Ross A. Hamilton, Yang Yu, David M. Lonard, Jin Wang, Shu-Ping Wang, David G. Edwards, Philip F. Lavere, Jiangyong Shao, Ping Yi, Antrix Jain, Sung Yun Jung, Anna Malovannaya, Shunqiang Li, Jieya Shao, Robert G. Roeder, Matthew J. Ellis, Jun Qin, Suzanne A. W. Fuqua, Bert W. O’Malley, Charles E. Foulds
Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10–40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.
A novel three-dimensional high-throughput screening approach identifies inducers of a mutant KRAS selective lethal phenotype Oncogene (IF 7.519) Pub Date : 2018-05-10 Smitha Kota, Shurong Hou, William Guerrant, Franck Madoux, Scott Troutman, Virneliz Fernandez-Vega, Nina Alekseeva, Neeharika Madala, Louis Scampavia, Joseph Kissil, Timothy P. Spicer
The RAS proteins are the most frequently mutated oncogenes in cancer, with highest frequency found in pancreatic, lung, and colon tumors. Moreover, the activity of RAS is required for the proliferation and/or survival of these tumor cells and thus represents a high-value target for therapeutic development. Direct targeting of RAS has proven challenging for multiple reasons stemming from the biology of the protein, the complexity of downstream effector pathways and upstream regulatory networks. Thus, significant efforts have been directed at identifying downstream targets on which RAS is dependent. These efforts have proven challenging, in part due to confounding factors such as reliance on two-dimensional adherent monolayer cell cultures that inadequately recapitulate the physiologic context to which cells are exposed in vivo. To overcome these issues, we implemented a high-throughput screening (HTS) approach using a spheroid-based 3-dimensional culture format, thought to more closely reflect conditions experienced by cells in vivo. Using isogenic cell pairs, differing in the status of KRAS, we identified Proscillaridin A as a selective inhibitor of cells harboring the oncogenic KRasG12V allele. Significantly, the identification of Proscillaridin A was facilitated by the 3D screening platform and would not have been discovered employing standard 2D culturing methods.
Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival Oncogene (IF 7.519) Pub Date : 2018-05-10 Andrew Baker, Debra Wyatt, Maurizio Bocchetta, Jun Li, Aleksandra Filipovic, Andrew Green, Daniel S. Peiffer, Suzanne Fuqua, Lucio Miele, Kathy S. Albain, Clodia Osipo
Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence. Notch signaling has been shown to promote BCSC survival and self-renewal. Trastuzumab-resistant cells have increased Notch-1 expression. Notch signaling drives cell proliferation in vitro and is required for tumor recurrence in vivo. We demonstrate herein a mechanism by which Notch-1 is required for trastuzumab resistance by repressing PTEN expression to contribute to activation of ERK1/2 signaling. Furthermore, Notch-1-mediated inhibition of PTEN is necessary for BCSC survival in vitro and in vivo. Inhibition of MEK1/2-ERK1/2 signaling in trastuzumab-resistant breast cancer cells mimics effects of Notch-1 knockdown on bulk cell proliferation and BCSC survival. These findings suggest that Notch-1 contributes to trastuzumab resistance by repressing PTEN and this may lead to hyperactivation of ERK1/2 signaling. Furthermore, high Notch-1 and low PTEN mRNA expression may predict poorer overall survival in women with breast cancer. Notch-1 protein expression predicts poorer survival in women with HER2+ breast cancer. These results support a potential future clinical trial combining anti-Notch-1 and anti-MEK/ERK therapy for trastuzumab-resistant breast cancer.
Loss-of-function of IFT88 determines metabolic phenotypes in thyroid cancer Oncogene (IF 7.519) Pub Date : 2018-05-10 Junguee Lee, Shinae Yi, Minho Won, Young Shin Song, Hyon-Seung Yi, Young Joo Park, Ki Cheol Park, Jung Tae Kim, Joon Young Chang, Min Joung Lee, Hae Joung Sul, Ji Eun Choi, Koon Soon Kim, Jukka Kero, Joon Kim, Minho Shong
Primary cilia are microtubule-based, dynamic organelles characterized by continuous assembly and disassembly. The intraflagellar transport (IFT) machinery, including IFT88 in cilia, is involved in the maintenance of bidirectional motility along the axonemes, which is required for ciliogenesis and functional competence. Cancer cells are frequently associated with loss of primary cilia and IFT functions. However, there is little information on the role of IFT88 or primary cilia in the metabolic remodeling of cancer cells. Therefore, we investigated the cellular and metabolic effects of the loss-of-function (LOF) mutations of IFT88/primary cilia in thyroid cancer cells. IFT88-deficient 8505C thyroid cancer cells were generated using the CRISPR/Cas9 system, and RNA-sequencing analysis was performed. LOF of the IFT88 gene resulted in a marked defect in ciliogenesis and mitochondrial oxidative function. Gene expression patterns in IFT88-deficient thyroid cancer cells favored glycolysis and lipid biosynthesis. However, LOF of IFT88/primary cilia did not promote thyroid cancer cell proliferation, migration, and invasion. The results suggest that IFT88/primary cilia play a role in metabolic reprogramming in thyroid cancer cells.
MASTL overexpression promotes chromosome instability and metastasis in breast cancer Oncogene (IF 7.519) Pub Date : 2018-05-10 Samuel Rogers, Rachael A. McCloy, Benjamin L. Parker, David Gallego-Ortega, Andrew M. K. Law, Venessa T. Chin, James R. W. Conway, Dirk Fey, Ewan K. A. Millar, Sandra O’Toole, Niantao Deng, Alexander Swarbrick, Paul D. Chastain, Anthony J. Cesare, Paul Timpson, C. Elizabeth Caldon, David R. Croucher, David E. James, D. Neil Watkins, Andrew Burgess
MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial–mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival.
Genome-wide profiling of microRNAs reveals novel insights into the interactions between H9N2 avian influenza virus and avian dendritic cells Oncogene (IF 7.519) Pub Date : 2018-05-10 Jian Lin, Jing Xia, Tian Zhang, Keyun Zhang, Qian Yang
The antigen-presenting ability of dendritic cells (DCs) plays an important and irreplaceable role in recognising and clearing viruses. Antiviral responses must rapidly defend against infection while minimising inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. MicroRNAs (microRNAs), small non-coding RNAs, can regulate mouse or avian DCs to inhibit the infection and replication of avian influenza virus (AIV). Here, we performed a global analysis to understand how avian DCs respond to H9N2 AIV and provide a potential mechanism to explain how avian microRNAs can defend against H9N2 AIV replication. First, we found that both active and inactive H9N2 AIV enhanced the ability of DCs to present antigens and activate T lymphocytes. Next, total microarray analyses suggested that H9N2 AIV stimulation involved protein localisation, nucleotide binding, leucocyte transendothelial migration and MAPK signalling. Moreover, we constructed 551 transcription factor (TF)–miRNA–mRNA loops based on the above analyses. Furthermore, we found that the haemagglutinin (HA) fragment, neither H5N1-HA or H9N2-HA, could not activate DCs, while truncated HA greatly increased the immune function of DCs by activating ERK and STAT3 signalling pathways. Lastly, our results not only suggested that gga-miR1644 targets muscleblind-like protein 2 (MBNL2) to enhance the ability of avian DCs to inhibit virus replication, but also suggested that gga-miR6675 targets the nuclear localisation sequence of polymerase basic protein 1 (PB1) to trigger the silencing of PB1 genes, resulting in the inhibition of H9N2 AIV replication. Altogether, our innovative study will shed new light on the role of avian microRNAs in evoking avian DCs and inhibiting virus replication.
Multi-nucleated cells use ROS to induce breast cancer chemo-resistance in vitro and in vivo Oncogene (IF 7.519) Pub Date : 2018-05-10 Aditya Parekh, Subhayan Das, Sheetal Parida, Chandan Kanta Das, Debabrata Dutta, Sanjaya K. Mallick, Pei-Hsun Wu, B. N. Prashanth Kumar, Rashmi Bharti, Goutam Dey, Kacoli Banerjee, Shashi Rajput, Deblina Bharadwaj, Ipsita Pal, Kaushik kumar Dey, Yetirajam Rajesh, Bikash Chandra Jena, Angana Biswas, Payel Banik, Anjan K. Pradhan, Swadesh K. Das, Amit Kumar Das, Santanu Dhara, Paul B. Fisher, Denis Wirtz, Gordon B. Mills, Mahitosh Mandal
Although there is a strong correlation between multinucleated cells (MNCs) and cancer chemo-resistance in variety of cancers, our understanding of how multinucleated cells modulate the tumor micro-environment is limited. We captured multinucleated cells from triple-negative chemo-resistant breast cancers cells in a time frame, where they do not proliferate but rather significantly regulate their micro-environment. We show that oxidatively stressed MNCs induce chemo-resistance in vitro and in vivo by secreting VEGF and MIF. These factors act through the RAS/MAPK pathway to induce chemo-resistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1α contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1α signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1α in future may help to abrogate drug resistance in breast cancer.
Dual inhibition of BCL-XL and MCL-1 is required to induce tumour regression in lung squamous cell carcinomas sensitive to FGFR inhibition Oncogene (IF 7.519) Pub Date : 2018-05-10 Clare E. Weeden, Casey Ah-Cann, Aliaksei Z. Holik, Julie Pasquet, Jean-Marc Garnier, Delphine Merino, Guillaume Lessene, Marie-Liesse Asselin-Labat
Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells. Using patient-derived xenografts and specific inhibitors of BCL-2, BCL-XL, and MCL-1, we identified a greater reliance of lung SqCC cells on BCL-XL and MCL-1 compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitors alone provided a survival benefit in combination FGFR therapy in vivo. Only triple BCL-XL, MCL-1, and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC. Our work therefore provides a rationale for the inhibition of MCL-1, BCL-XL, and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.
Transactivation of human endogenous retrovirus K (HERV-K) by KSHV promotes Kaposi’s sarcoma development Oncogene (IF 7.519) Pub Date : 2018-05-10 Lu Dai, Luis Del Valle, Wendell Miley, Denise Whitby, Augusto C. Ochoa, Erik K. Flemington, Zhiqiang Qin
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers such as Kaposi’s sarcoma (KS), which represents the most common AIDS-associated malignancy that lacks effective treatment options. Despite its clear role in AIDS malignancies, the fact that only a small set of KSHV-infected patients will eventually develop these tumors implies that additional co-factors are required for the development of KSHV-related cancers. In the current study, we demonstrate for the first time that KSHV de novo infection or viral latent proteins are able to transactivate human endogenous retrovirus K (HERV-K) through a variety of cellular signaling pathways and transcriptional factors. Moreover, we found that HERV-K transactivation, particularly activation of its encoded oncogenic NP9 protein, plays an important role in KSHV pathogenesis and tumorigenesis in vitro and in vivo. Our data provide innovative insights into the mechanisms of HERV-K transactivation contributing to viral oncogenesis, which may represent a promising target for KS treatment.
Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades Oncogene (IF 7.519) Pub Date : 2018-05-03 Ningning Li, Ying Zhang, Kastytis Sidlauskas, Matthew Ellis, Ian Evans, Paul Frankel, Joanne Lau, Tedani El-Hassan, Loredana Guglielmi, Jessica Broni, Angela Richard-Loendt, Sebastian Brandner
To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas.
Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer Oncogene (IF 7.519) Pub Date : 2018-05-03 Sarah Yoon, Eun-Ju Lee, Ji-Hye Choi, Taek Chung, Do Young Kim, Jong-Yeop Im, Myung-Ho Bae, Jung-Hee Kwon, Hyuk-Hoon Kim, Hyung Chul Kim, Young Nyun Park, Hee-Jung Wang, Hyun Goo Woo
Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.
Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics Oncogene (IF 7.519) Pub Date : 2018-05-03 Ellen Puré, Rachel Blomberg
Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments. Yet despite this growing field of research, our knowledge of FAP’s basic biology and functional roles in various cancers has lagged behind its use as a tumor-stromal marker. In this review, we summarize and analyze recent advances in understanding the functions of FAP in cancer, most notably its prognostic value in various tumor types, cellular effects on various cell types, and potential as a therapeutic target. We highlight outstanding questions in the field, the answers to which could shape preclinical and clinical studies of FAP.
Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation Oncogene (IF 7.519) Pub Date : 2018-05-03 Dinesh K. Ahirwar, Mohd W. Nasser, Madhu M. Ouseph, Mohamad Elbaz, Maria C. Cuitiño, Raleigh D. Kladney, Sanjay Varikuti, Kirti Kaul, Abhay R. Satoskar, Bhuvaneswari Ramaswamy, Xiaoli Zhang, Michael C. Ostrowski, Gustavo Leone, Ramesh K. Ganju
The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.
Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness Oncogene (IF 7.519) Pub Date : 2018-05-03 Gilles Rademaker, Vincent Hennequière, Laura Brohée, Marie-Julie Nokin, Pierre Lovinfosse, Florence Durieux, Stéphanie Gofflot, Justine Bellier, Brunella Costanza, Michael Herfs, Raphael Peiffer, Lucien Bettendorff, Christophe Deroanne, Marc Thiry, Philippe Delvenne, Roland Hustinx, Akeila Bellahcène, Vincent Castronovo, Olivier Peulen
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism.
HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells Oncogene (IF 7.519) Pub Date : 2018-05-03 Matthew C. White, Rebecca D. Schroeder, Keyi Zhu, Katherine Xiong, David J. McConkey
Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2α phosphorylation among a panel of ten human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2α kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2α phosphorylation, conferring a high degree of sensitivity to bortezomib. These bortezomib-sensitive cells exhibited impaired translation attenuation followed by toxic accumulation of protein aggregates and reactive oxygen species (ROS), whereas the bortezomib-resistant cell lines displayed increased phosphorylation of eIF2α, decreased translation, few protein aggregates, and minimal ROS production. Importantly, we identified HRI as the primary bortezomib-activated eIF2α kinase, and demonstrated that HRI knockdown promoted cell death in the bortezomib-resistant cells. Overall, our data implicate inducible HRI-mediated phosphorylation of eIF2α as a central cytoprotective mechanism following exposure to bortezomib and provide proof-of-concept for the development of HRI inhibitors to overcome proteasome inhibitor resistance.
Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin β3 Oncogene (IF 7.519) Pub Date : 2018-05-02 Jinnan Yue, Dacheng Lv, Caiyun Wang, Ling Li, Qingnan Zhao, Hongzhuan Chen, Lu Xu
All lung cancers patients with epidermal growth factor receptor (EGFR) mutation inevitably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In up to 30% of cases, the mechanism underlying acquired resistance remains unknown. MicroRNAs (miRNAs) is a group of small non-coding RNAs commonly dysregulated in human cancers and have been implicated in therapy resistance. The aim of this study was to understand the roles of novel miRNAs in acquired EGFR TKI resistance in EGFR-mutant non-small cell lung cancer (NSCLC). Here, we reported the evidence of miR-483-3p silencing and epithelial-to-mesenchymal transition (EMT) phenotype in both in vitro and in vivo EGFR-mutant NSCLC models with acquired resistance to gefitinib. In those tumor models, forced expression of miR-483-3p efficiently increased sensitivity of gefitinib-resistant lung cancer cells to gefitinib by inhibiting proliferation and promoting apoptosis. Moreover, miR-483-3p reversed EMT and inhibited migration, invasion, and metastasis of gefitinib-resistant lung cancer cells. Mechanistically, miR-483-3p directly targeted integrin β3, and thus repressed downstream FAK/Erk signaling pathway. Furthermore, the silencing of miR-483-3p in gefitinib-resistant lung cancer cells was due to hypermethylation of its own promoter. Taken together, our data identify miR-483-3p as a promising target for combination therapy to overcome acquired EGFR TKI resistance in EGFR-mutant NSCLC.
Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis Oncogene (IF 7.519) Pub Date : 2018-05-02 Rie Imamaki, Kazuko Ogawa, Yasuhiko Kizuka, Yusuke Komi, Soichi Kojima, Norihiro Kotani, Koichi Honke, Takashi Honda, Naoyuki Taniguchi, Shinobu Kitazume
Most of the angiogenesis inhibitors clinically used in cancer treatment target the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. However, the current strategies for treating angiogenesis have limited efficacy. The issue of how to treat angiogenesis and endothelial dysfunction in cancer remains a matter of substantial debate. Here we demonstrate a glycosylation-dependent regulatory mechanism for tumor angiogenesis. St6gal1−/− mice, lacking the α2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis. In a previous study, St6gal1−/− endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that cooperative functionality of PECAM-VEGFR2-integrin β3 was disturbed in St6gal1−/− mice. First, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that the absence of α2,6-sialic acid leads to dysregulated integrin signaling. Notably, ectopic expression of PECAM increased cell surface integrin-β3, indicating that the reduction of cell surface integrin-β3 involves loss-of-endothelial PECAM. The results suggest that the cell surface stability of these glycoproteins is significantly reduced by the lack of α2,6-sialic acid, leading to abnormal signal transduction. The present findings highlight that α2,6-sialylation is critically involved in endothelial survival by controlling the cell surface stability and signal transduction of angiogenic molecules, and could be a novel target for anti-angiogenesis therapy.
A modified gene trap approach for improved high-throughput cancer drug discovery Oncogene (IF 7.519) Pub Date : 2018-05-02 Shelli M. Morris, Andrew J. Mhyre, Savanna S. Carmack, Carrie H. Myers, Connor Burns, Wenjuan Ye, Marc Ferrer, James M. Olson, Richard A. Klinghoffer
While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development of robust cell-based assays in relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present a modified gene trap approach to efficiently generate pathway-specific reporters that result in a robust “on” signal when the pathway of interest is inhibited. In this proof-of-concept study, we used vemurafenib and trametinib to identify traps that specifically detect inhibition of the mitogen-activated protein kinase (MAPK) pathway in a model of BRAFV600E driven human malignant melanoma. We demonstrate that insertion of our trap into particular loci results in remarkably specific detection of MAPK pathway inhibitors over compounds targeting any other pathway or cellular function. The accuracy of our approach was highlighted in a pilot screen of ~6000 compounds where 40 actives were detected, including 18 MEK, 10 RAF, and 3 ERK inhibitors along with a few compounds representing previously under-characterized inhibitors of the MAPK pathway. One such compound, bafetinib, a second generation BCR/ABL inhibitor, reduced phosphorylation of ERK and when combined with trametinib, both in vitro and in vivo, reduced growth of vemurafenib resistant melanoma cells. While piloted in a model of BRAF-driven melanoma, our results set the stage for using this approach to rapidly generate reporters against any transcriptionally active pathway across a wide variety of disease-relevant cell-based models to expedite drug discovery efforts.
Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia Oncogene (IF 7.519) Pub Date : 2018-05-02 Astrid A. Glück, Eleonora Orlando, Dominic Leiser, Michaela Poliaková, Lluís Nisa, Aurélie Quintin, Jacopo Gavini, Deborah M. Stroka, Sabina Berezowska, Lukas Bubendorf, Andree Blaukat, Daniel M. Aebersold, Michaela Medová, Yitzhak Zimmer
Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia-inducible factor 1α (HIF-1α)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1α system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET-driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1α and its various downstream targets. Mechanistically, we provide evidence that MET regulates HIF-1α levels through a protein translation mechanism that relies on phosphorylation modulation of the eukaryotic initiation factor 4G1 (eIF4G1) on serine 1232 (Ser-1232). Targeted phosphoproteomics data demonstrate a significant drop in eIF4G1 Ser-1232 phosphorylation following MET targeting, which is linked to an increased affinity between eIF4G1 and eIF4E. Since phosphorylation of eIF4G1 on Ser-1232 is largely mediated through mitogen-activated protein kinase (MAPK), we show that expression of a constitutively active K-RAS variant is sufficient to abrogate the inhibitory effect of MET targeting on the HIF-1α pathway with subsequent resistance of tumor cells to MET targeting under hypoxic conditions. Analysis of The Cancer Genome Atlas data demonstrates frequent co-expression of MET, HIF-1α and eIF4G1 in various solid tumors and its impact on disease-free survival of non-small cell lung cancer patients. Clinical relevance of the MET-eIF4G1-HIF-1α pathway is further supported by a co-occurrence of their expression in common tumor regions of individual lung cancer patients.
Antagonizing CD105 enhances radiation sensitivity in prostate cancer Oncogene (IF 7.519) Pub Date : 2018-05-02 Anisha Madhav, Allen Andres, Frank Duong, Rajeev Mishra, Subhash Haldar, Zhenqiu Liu, Bryan Angara, Roberta Gottlieb, Zachary S. Zumsteg, Neil A. Bhowmick
Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation-resistant disease is an obstacle for nearly 30–50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-β signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1α activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1’s role on p53 and PGC-1α with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value = 10−9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers.
DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer Oncogene (IF 7.519) Pub Date : 2018-05-02 He Cui, Ying Hu, Didi Guo, Aifeng Zhang, Yuejun Gu, Shaodan Zhang, Chengcheng Zhao, Pihai Gong, Xiaohui Shen, Yiping Li, Huazhang Wu, Ling Wang, Zhujiang Zhao, Hong Fan
DNA methyltransferase 3A (DNMT3A) has been recognised as a key element of epigenetic regulation in normal development, and the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours remain unknown, although abnormal expression has gained widespread attention in these cancers. Here, we show that DNMT3A isoform b (DNMT3Ab), a member of the DNMT3A isoform family, is critical for directing epithelial–mesenchymal transition (EMT)-associated metastasis in gastric cancer (GC). DNMT3Ab is positively linked to tumour-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis in GC patients. Overexpression of DNMT3Ab promotes GC cell migration and invasion as well as EMT through repression of E-cadherin. Meanwhile, DNMT3Ab promotes lung metastasis of GC in vivo. Mechanistic studies indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF-β-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. Further, gene expression profiling analysis indicates that multiple metastasis-associated genes and oncogenic signalling pathways are regulated in response to DNMT3Ab overexpression. These results identify DNMT3Ab as a crucial regulator of metastasis-related genes in GC. Targeting the DNMT3Ab/Snail/E-cadherin axis may provide a promising therapeutic strategy in the treatment of metastatic GC with high DNMT3Ab expression.
Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-β exposure Oncogene (IF 7.519) Pub Date : 2018-05-01 Jesse Handler, Jane Cullis, Antonina Avanzi, Emily A. Vucic, Dafna Bar-Sagi
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease and a major health problem in the United States. While the cytokine TGF-β has been implicated in PDAC development, it can exert both pro-tumorigenic and anti-tumorigenic effects that are highly context dependent and incompletely understood. Using three-dimensional (3D) cultures of KrasG12D-expressing mouse pancreatic epithelial cells we demonstrated that while exposure to exogenous TGF-β induced growth arrest of the KrasG12D cells, its subsequent removal allowed the cells to enter a hyper-proliferative, partially mesenchymal (PM), and progenitor-like state. This state was highly stable and was maintained by autocrine TGF-β signaling. While untreated KrasG12D cells formed cystic lesions in vivo, PM cells formed ductal structures resembling human PanINs, suggesting that they had attained increased oncogenic potential. Supporting this hypothesis, we determined that the PM cells share salient molecular and phenotypic features with the quasi-mesenchymal/squamous subtype of human PDAC, which has the worst prognosis of any of the recently identified subtypes. Transient pulses of TGF-β have been observed during pancreatitis, a major risk factor for PDAC. Our data suggest that transient TGF-β exposure is sufficient to induce the acquisition of stable PDAC-associated phenotypes in pre-neoplastic KrasG12D cells, providing novel molecular insight into the complex role of TGF-β in tumorigenesis.
Ubiquitylation and degradation of adenomatous polyposis coli by MKRN1 enhances Wnt/β-catenin signaling Oncogene (IF 7.519) Pub Date : 2018-05-01 Hae-Kyung Lee, Eun-Woo Lee, Jinho Seo, Manhyung Jeong, Seon-Hyeong Lee, Soo-Youl Kim, Eek-Hoon Jho, Chel Hun Choi, Joon-Yong Chung, Jaewhan Song
The adenomatous polyposis coli (APC) protein has a tumor-suppressor function by acting as a negative regulator of the Wnt signaling pathway. While its role as a tumor suppressor is well-defined, the post-translational modifications that regulate APC stability are not fully understood. Here we showed that MKRN1, an E3 ligase, could directly interact with and ubiquitylate APC, promoting its proteasomal degradation. In contrast, an E3 ligase-defective MKRN1 mutant was no longer capable of regulating APC, indicating that its E3 ligase activity is required for APC regulation by MKRN1. Strengthening these results, MKRN1 ablation resulted in reduced β-catenin activity and decreased expression of Wnt target genes. The ability of the Wnt-dependent pathway to induce cancer cell proliferation, migration, and invasion was impaired by MKRN1 depletion, but restored by simultaneous APC knockdown. Taken together, these results demonstrate that MKRN1 functions as a novel E3 ligase of APC that positively regulates Wnt/β-catenin-mediated biological processes.
Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis Oncogene (IF 7.519) Pub Date : 2018-05-01 Ralph Klose, M. Gordian Adam, Eva-Maria Weis, Iris Moll, Joycelyn Wüstehube-Lausch, Fabian Tetzlaff, Chio Oka, Michael Ehrmann, Andreas Fischer
The serine protease HTRA1 is involved in several vascular diseases and its expression is often deregulated in cancer. We aimed at identifying how HTRA1 in the vasculature affects tumor growth. Here we report that silencing of HTRA1 in cultured endothelial cells increased migration rate and tube formation, whereas forced HTRA1 expression impaired sprouting angiogenesis. Mechanistically, endothelial HTRA1 expression enhanced Delta/Notch signaling by reducing the amount of the weak Notch ligand JAG1. HTRA1 physically interacted with JAG1 and cleaved it within the intracellular domain, leading to protein degradation. Expression of a constitutive active Notch1 prevented the hypersprouting phenotype upon silencing of HTRA1. In HtrA1-deficient mice, endothelial Notch signaling was diminished and isolated endothelial cells had increased expression of VEGF receptor-2. Growth of syngeneic tumors was strongly impaired in HtrA1−/− mice. The tumor vasculature was much denser in HtrA1−/− mice and less covered with mural cells. This chaotic and immature vascular network was poorly functional as indicated by large hypoxic tumor areas and low tumor cell proliferation rates. In summary, inhibition of HTRA1 in the tumor stroma impaired tumor progression by deregulating angiogenesis.
Intermittent hypoxia induces a metastatic phenotype in breast cancer Oncogene (IF 7.519) Pub Date : 2018-05-01 Anna Chen, Jaclyn Sceneay, Nathan Gödde, Tanja Kinwel, Sunyoung Ham, Erik W Thompson, Patrick O Humbert, Andreas Möller
Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor-supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal diversity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth.
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