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- W3163930361 abstract "Abstract Background : The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of second-generation 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. Methods : TRIM59 expression was evaluated in PCa samples from patients at first diagnosis or at relapse stage post ARPI treatment by immunohistochemistry; in vitro effects of TRIM59 were determined by cell proliferation, sphere formation and cell migration assays; while in vivo analysis was performed using subcutaneous tumor model. Western blot, qPCR assay, dual luciferase assessment, chromatin immunoprecipitation and RNA sequencing were applied for mechanistic exploration. Results : 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. Conclusion: 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." @default.
- W3163930361 created "2021-05-24" @default.
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- W3163930361 date "2021-05-07" @default.
- W3163930361 modified "2023-10-16" @default.
- W3163930361 title "TRIM59 is Suppressed by Androgen Receptor and Acts to Promote Lineage Plasticity and Neuroendocrine Differentiation in Prostate Cancer" @default.
- W3163930361 doi "https://doi.org/10.21203/rs.3.rs-470260/v1" @default.
- W3163930361 hasPublicationYear "2021" @default.
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