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.
Similar content being viewed by others
Data availability
RNA sequencing data are available at National Genomics Data Center accession number HRA003902 under Bioproject accession number PRJCA010762.
References
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.
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.
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.
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.
Wang ZA, Shen MM. Revisiting the concept of cancer stem cells in prostate cancer. Oncogene. 2011;30:1261–71.
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.
Davies AH, Beltran H, Zoubeidi A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat Rev Urol. 2018;15:271–86.
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.
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.
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.
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.
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.
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.
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.
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.
MYCN transforms prostate epithelium to neuroendocrine prostate cancer. Cancer Discov. 2016;6:OF19.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Author information
Authors and Affiliations
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Consent for publication
All subjects gave written informed consent.
Ethics approval and consent to participate
All animal experiments were approved by the Institutional Animal Care and Use Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-022-02498-1
- Springer Nature Limited
This article is cited by
-
ΔPSap4#5 surface-functionalized abiraterone-loaded nanoparticle successfully inhibits carcinogen-induced prostate cancer in mice: a mechanistic investigation
Cancer Nanotechnology (2023)
-
Therapeutic, diagnostic and prognostic values of TRIM proteins in prostate cancer
Pharmacological Reports (2023)