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TRIM59 is suppressed by androgen receptor and acts to promote lineage plasticity and treatment-induced neuroendocrine differentiation in prostate cancer

Oncogene volume 42, pages 559–571 (2023)Cite this article

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Abstract

The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of secondgeneration androgen receptor (AR) pathway inhibitors (ARPIs). Neuroendocrine differentiation (NED) is closely associated with ARPI treatment failure and poor prognosis in prostate cancer (PCa) patients. However, the molecular mechanisms of NED are not fully understood. Here we report that upregulation of TRIM59, a TRIM family protein, is strongly correlated with ARPI treatment mediated NED and shorter patient survival in PCas. AR binds to TRIM59 promoter and represses its transcription. ARPI treatment leads to a reversal of repressive epigenetic modifications on TRIM59 gene and the transcriptional restraint on TRIM59 by AR. Upregulated TRIM59 then drives the NED of PCa by enhancing the degradation of RB1 and P53 and upregulating downstream lineage plasticity-promoting transcription factor SOX2. Altogether, TRIM59 is negatively regulated by AR and acts as a key driver for NED in PCas. Our study provides a novel prognostic marker for PCas and shed new light on the molecular pathogenesis of t-NEPC, a deadly variant of PCa.

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Fig. 1: TRIM59 is highly expressed in castration-resistant neuroendocrine prostate cancer and associated with poor disease outcomes.
Fig. 2: TRIM59 is negatively correlated with AR signaling in human prostate cancers.
Fig. 3: AR suppresses the transcription of TRIM59 in prostate cancer cells.
Fig. 4: TRIM59 significantly promotes castration resistance in PCa cells.
Fig. 5: TRIM59 silencing suppresses CRPC cell proliferation, migration, and xenograft tumor growth.
Fig. 6: TRIM59 drives the NED of PCa.
Fig. 7: TRIM59 promotes degradation of P53 and RB1 and upregulates SOX2.
Fig. 8: Schema illustrating TRIM59 as an AR-suppressed driver in the neuroendocrine differentiation of prostate cancer.

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Data availability

RNA sequencing data are available at National Genomics Data Center accession number HRA003902 under Bioproject accession number PRJCA010762.

References

  1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    Article  CAS  PubMed  Google Scholar 

  3. Aggarwal R, Huang J, Alumkal JJ, Zhang L, Feng FY, Thomas GV, et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J Clin Oncol: Off J Am Soc Clin Oncol. 2018;36:2492–503.

    Article  CAS  Google Scholar 

  4. Aparicio AM, Harzstark AL, Corn PG, Wen S, Araujo JC, Tu S-M, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;19:3621–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang ZA, Shen MM. Revisiting the concept of cancer stem cells in prostate cancer. Oncogene. 2011;30:1261–71.

    Article  PubMed  Google Scholar 

  6. Wang ZA, Mitrofanova A, Bergren SK, Abate-Shen C, Cardiff RD, Califano A, et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol. 2013;15:274–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15:271–86.

    Article  CAS  PubMed  Google Scholar 

  8. Quintanal-Villalonga Á, Chan JM, Yu HA, Pe’er D, Sawyers CL, Sen T, et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat Rev Clin Oncol. 2020;17:360–71.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2014;20:890–903.

    Article  CAS  Google Scholar 

  12. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355:84–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y, et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discov. 2017;7:736–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bishop JL, Thaper D, Vahid S, Davies A, Ketola K, Kuruma H, et al. The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 2017;7:54–71.

    Article  CAS  PubMed  Google Scholar 

  15. Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1:487–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. MYCN transforms prostate epithelium to neuroendocrine prostate cancer. Cancer Discov. 2016;6:OF19.

  17. Berger A, Brady NJ, Bareja R, Robinson B, Conteduca V, Augello MA, et al. N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. J Clin Investig. 2019;130:3924–40.

    Article  Google Scholar 

  18. Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell. 2016;30:563–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, McCaffrey EF, et al. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell. 2016;29:536–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yin Y, Xu L, Chang Y, Zeng T, Chen X, Wang A, et al. N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway. Mol Cancer. 2019;18:11.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li Y, Donmez N, Sahinalp C, Xie N, Wang Y, Xue H, et al. SRRM4 drives neuroendocrine transdifferentiation of prostate adenocarcinoma under androgen receptor pathway inhibition. Eur Urol. 2017;71:68–78.

    Article  CAS  PubMed  Google Scholar 

  22. Ozato K, Shin DM, Chang TH, Morse HC 3rd. TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol. 2008;8:849–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tomar D, Singh R. TRIM family proteins: emerging class of RING E3 ligases as regulator of NF-kappaB pathway. Biol Cell. 2015;107:22–40.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou Z, Ji Z, Wang Y, Li J, Cao H, Zhu HH, et al. TRIM59 is up-regulated in gastric tumors, promoting ubiquitination and degradation of p53. Gastroenterology. 2014;147:1043–54.

    Article  CAS  PubMed  Google Scholar 

  25. Valiyeva F, Jiang F, Elmaadawi A, Moussa M, Yee SP, Raptis L, et al. Characterization of the oncogenic activity of the novel TRIM59 gene in mouse cancer models. Mol Cancer Ther. 2011;10:1229–40.

    Article  CAS  PubMed  Google Scholar 

  26. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cai C, He HH, Chen S, Coleman I, Wang H, Fang Z, et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell. 2011;20:457–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cai C, He HH, Gao S, Chen S, Yu Z, Gao Y, et al. Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Rep. 2014;9:1618–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Uysal-Onganer P, Kawano Y, Caro M, Walker MM, Diez S, Darrington RS, et al. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells. Mol Cancer. 2010;9:55.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Sheng Y, Ji Z, Zhao H, Wang J, Cheng C, Xu W, et al. Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells. Cell Prolif. 2019;52:e12611.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Su W, Han HH, Wang Y, Zhang B, Zhou B, Cheng Y, et al. The polycomb repressor complex 1 drives double-negative prostate cancer metastasis by coordinating stemness and immune suppression. Cancer Cell. 2019;36:139–55.e110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chu M, Chang Y, Li P, Guo Y, Zhang K, Gao W. Androgen receptor is negatively correlated with the methylation-mediated transcriptional repression of miR-375 in human prostate cancer cells. Oncol Rep. 2014;31:34–40.

    Article  CAS  PubMed  Google Scholar 

  33. Sang Y, Li Y, Song L, Alvarez AA, Zhang W, Lv D, et al. TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3. Cancer Res. 2018;78:1792–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Olsen JR, Azeem W, Hellem MR, Marvyin K, Hua Y, Qu Y, et al. Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes. BMC Cancer. 2016;16:377.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

The study was supported by funds to HHZ from the National Natural Science Foundation of China (NSFC32022021 and NSFC81972404), Shanghai Pilot Program for Basic Research - Shanghai Jiao Tong University (21TQ1400225), the Program of Shanghai Academic/Technology Research Leader (21XD1422300), the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine Grant Support (20181706), and the Innovative research team of high-level local universities in Shanghai. The study was also supported by funds to Department of Urology, Ren Ji hospital from National Natural Science Foundation of China (82002710, 81772742), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20191906); Shanghai Sailing Program (20YF1425300).

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Author notes

  1. These authors contributed equally: Liancheng Fan, Yiming Gong.

Authors and Affiliations

  1. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Liancheng Fan, Yiming Gong, Baijun Dong, Helen He Zhu & Wei Xue

  2. State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center & Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Yuman He, Wei-Qiang Gao & Helen He Zhu

  3. Department of Urological Sciences, Vancouver Prostate Cancer Centre, University of BC, Vancouver, BC, V6H 3Z6, Canada

    Xuesen Dong

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Contributions

WX, HHZ, BD, LF, and YG designed the study and wrote the manuscript; LF and YG performed all the experiments and data analysis with the help of YH, QW, and WG.; WX and BD provided clinical samples and patient information; all authors read and approved the final manuscript.

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Correspondence to Baijun Dong, Helen He Zhu or Wei Xue.

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All animal experiments were approved by the Institutional Animal Care and Use Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University.

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Fan, L., Gong, Y., He, Y. et al. TRIM59 is suppressed by androgen receptor and acts to promote lineage plasticity and treatment-induced neuroendocrine differentiation in prostate cancer. Oncogene 42, 559–571 (2023). https://doi.org/10.1038/s41388-022-02498-1

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