Abstract
CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nat Rev Dis Prim. 2017;3:17022.
Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15:25–41.
Choi W, Ochoa A, Mcconkey DJ, Aine M, Höglund M, Kim WY, et al. Genetic alterations in the molecular subtypes of bladder cancer: illustration in the Cancer Genome Atlas dataset. Eur Urol. 2017;72:354–65.
Network CGA. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase–AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004.
Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 2015;67:11–28.
Mensah FA, Blaize JP, Bryan LJ. Spotlight on copanlisib and its potential in the treatment of relapsed/refractory follicular lymphoma: evidence to date. Onco Targets Ther. 2018;11:4817–27.
Caino MC, Ghosh JC, Chae YC, Vaira V, Rivadeneira DB, Faversani A, et al. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proc Natl Acad Sci USA. 2015;112:8638–43.
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008;8:187–98.
Paplomata E, O’Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014;6:154–66.
Hu H, Yang Y, Ji Q, Zhao W, Jiang B, Liu R, et al. CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis. Cancer Cell. 2012;22:781–95.
Wei Z, Guo H, Liu Z, Zhang X, Liu Q, Qian Y, et al. CUL4B impedes stress-induced cellular senescence by dampening a p53-reactive oxygen species positive feedback loop. Free Radic Bio Med. 2015;79:1–13.
Zou Y, Mi J, Cui J, Lu D, Zhang X, Guo C, et al. Characterization of nuclear localization signal in the N terminus of CUL4B and its essential role in cyclin E degradation and cell cycle progression. J Biol Chem. 2009;284:33320–32.
Hannah J, Zhou P. Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B. Gene. 2015;573:33–45.
Li P, Song Y, Zan W, Qin L, Han S, Jiang B, et al. Lack of CUL4B in adipocytes promotes PPARγ-mediated adipose tissue expansion and insulin sensitivity. Diabetes.2017;66:300–13.
Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, et al. Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am J Hum Genet. 2007;80:561–6.
Tarpey PS, Raymond FL, O’Meara S, Edkins S, Teague J, Butler A, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet. 2007;80:345–52.
Yuan J, Han B, Hu H, Qian Y, Liu Z, Wei Z, et al. CUL4B activates Wnt/β-catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists. J Pathol. 2015;235:784–95.
Qi M, Jiao M, Li X, Hu J, Wang L, Zou Y, et al. CUL4B promotes gastric cancer invasion and metastasis-involvement of upregulation of HER2. Oncogene. 2017;37:1075–85.
Mi J, Zou Y, Lin X, Lu J, Liu X, Zhao H, et al. Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma. Mol Oncol. 2017;11:305–19.
Qian Y, Yuan J, Hu H, Yang Q, Li J, Zhang S, et al. The CUL4B/AKT/β-catenin axis restricts the accumulation of myeloid-derived suppressor cells to prohibit the establishment of a tumor permissive microenvironment. Cancer Res. 2015;75:5070–83.
Xu Z, Li L, Qian Y, Song Y, Qin L, Duan Y, et al. Upregulation of IL-6 in CUL4B-deficient myeloid-derived suppressive cells increases the aggressiveness of cancer cells. Oncogene. 2019;38:5860–72.
Ji Q, Hu H, Yang F, Yuan J, Yang Y, Jiang L, et al. CRL4B interacts with and coordinates the SIN3A-HDAC complex to repress CDKN1A and drive cell cycle progression. J Cell Sci. 2014;127:4679–91.
Yang Y, Liu R, Qiu R, Zheng Y, Huang W, Hu H, et al. CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene. 2015;34:104–18.
Mao XW, Xiao JQ, Xu G, Li ZY, Wu HF, Li Y, et al. CUL4B promotes bladder cancer metastasis and induces epithelial-to-mesenchymal transition by activating the Wnt/β-catenin signaling pathway. Oncotarget. 2017;8:77241–53.
BubenÃk J, BareÅ¡ová M, Viklický V, Jakoubková J, Sainerová H, Donner J. Established cell line of urinary bladder carcinoma (T24) containing tumour-specific antigen. Int J Cancer. 1973;11:765–73.
See WA, Xu Y, Gee K, Severson C, Cohen MB, Ladehoff D. Transurethral bladder tumor resection alters fibronectin expression in transitional carcinoma cell lines. J Urol. 1997;157:1136–43.
Kuwada M, Chihara Y, Luo Y, Li X, Nishiguchi Y, Fujiwara R, et al. Pro-chemotherapeutic effects of antibody against extracellular domain of claudin-4 in bladder cancer. Cancer Lett. 2015;369:212–21.
Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34.
Sheng S, Qiao M, Pardee AB. Metastasis and AKT activation. Cell Cycle. 2008;7:2991–6.
Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, et al. Activation of NF-κB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene. 2008;26:7445–56.
Zhao M, Qi M, Li X, Hu J, Zhang J, Jiao M, et al. CUL4B/miR-33b/C-MYC axis promotes prostate cancer progression. Prostate. 2019;79:480–8.
Zou Y, Mi J, Wang W, Lu J, Zhao W, Liu Z, et al. CUL4B promotes replication licensing by up-regulating the CDK2-CDC6 cascade. J Cell Biol. 2013;200:743–56.
El-Daly SM, Abba ML, Patil N, Allgayer H. miRs-134 and -370 function as tumor suppressors in colorectal cancer by independently suppressing EGFR and PI3K signalling. Sci Rep. 2016;6:24720.
Adi Harel S, Bossel Ben-Moshe N, Aylon Y, Bublik DR, Moskovits N, Toperoff G, et al. Reactivation of epigenetically silenced miR-512 and miR-373 sensitizes lung cancer cells to cisplatin and restricts tumor growth. Cell Death Differ. 2015;22:1328–40.
Qi M, Hu J, Cui Y, Jiao M, Feng T, Li X, et al. CUL4B promotes prostate cancer progression by forming positive feedback loop with SOX4. Oncogenesis. 2019;8:23.
Zhang Y, Khoo HE, Esuvaranathan K. Effects of bacillus Calmette–Guerin and interferon-alpha-2B on human bladder cancer in vitro. Int J Cancer. 1997;71:851–7.
Ler LD, Ghosh S, Chai X, Thike AA, Heng HL, Siew EY, et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci Transl Med. 2017;9:eaai8312.
Lang A, Yilmaz M, Hader C, Murday S, Kunz X, Wagner N, et al. Contingencies of UTX/KDM6A action in urothelial carcinoma. Cancers. 2019;11:E481.
Earl J, Rico D, Carrillo-de-Santa-Pau E, Rodriguez-Santiago B, Mendez-Pertuz M, Auer H, et al. The UBC-40 urothelial bladder cancer cell line index: a genomic resource for functional studies. BMC Genom. 2015;16:403.
Solomon DA, Kim JS, Bondaruk J, Shariat SF, Wang ZF, Elkahloun AG, et al. Frequent truncating mutations of STAG2 in bladder cancer. Nat Genet. 2013;45:1428–30.
Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16:21–32.
Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169:381–405.
Cicenas J. The potential role of Akt phosphorylation in human cancers. Int J Biol Markers. 2008;23:1–9.
Platt FM, Hurst CD, Taylor CF, Gregory WM, Patricia H, Knowles MA. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009;15:6008–17.
Yardena S, Zhenghe W, Alberto B, Natalie S, Janine P, Steve S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.
Lang Q, Ling C. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun. 2012;426:247–52.
Liu J, Li Q, Li R, Ren P, Dong S. MicroRNA-363-3p inhibits papillary thyroid carcinoma progression by targeting PIK3CA. Am J Cancer Res. 2017;7:148–58.
Yu QQ, Wu H, Huang X, Shen H, Shu YQ, Zhang B, et al. MiR-1 targets PIK3CA and inhibits tumorigenic properties of A549 cells. Biomed Pharmacother. 2014;68:155–61.
Segovia C, MartÃnez-Fernández M, Dueñas M, Rubio C. Opposing roles of PIK3CA gene alterations to EZH2 signaling in nonmuscle-invasive bladder cancer. Oncotarget. 2016;6:10531–42.
Acknowledgements
The authors would like to thank Dr M. Oren for kindly providing psiCHECK2 reporter plasmids containing the 3′UTR wide-type and mutant sequences of PIK3CA. This work was supported by the National Natural Science Foundation of China (81330050 and 81571523 to YG, 31671427 to YZ, 81770660 to GL); the Natural Science Foundation of Shandong Province (ZR2016HZ01 to YG); the Key Research and Development Program of Shandong Province (2016ZDJS07A08 to YG); and Young Scholars Program of Shandong University (to YZ).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liu, X., Cui, J., Gong, L. et al. The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer. Oncogene 39, 3588–3603 (2020). https://doi.org/10.1038/s41388-020-1236-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-020-1236-1
This article is cited by
-
From clinical management to personalized medicine: novel therapeutic approaches for ovarian clear cell cancer
Journal of Ovarian Research (2024)
-
CUL4B functions as a tumor suppressor in KRAS-driven lung tumors by inhibiting the recruitment of myeloid-derived suppressor cells
Oncogene (2023)
-
Comprehensive analysis of N6-methyladenosine regulators with the tumor immune landscape and correlation between the insulin-like growth factor 2 mRNA-binding protein 3 and programmed death ligand 1 in bladder cancer
Cancer Cell International (2022)
-
Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma
Molecular Cancer (2022)
-
Identification of different proteins binding to Na, K-ATPase α1 in LPS-induced ARDS cell model by proteomic analysis
Proteome Science (2022)