Mp05-04 Pgc1 as a Downstream Effector of Kdm5b Promotes the Progression of Androgen Receptor-Positive and Androgen Receptor-Negative Prostate Cancers

You have accessJournal of UrologyProstate Cancer: Basic Research AS A DOWNSTREAM EFFECTOR OF KDM5B PROMOTES THE PROGRESSION OF ANDROGEN RECEPTOR-POSITIVE AND ANDROGEN RECEPTOR-NEGATIVE PROSTATE CANCERS Yuki Teramoto, Zhiming Yang, and Hiroshi Miyamoto Yuki TeramotoYuki Teramoto , Zhiming YangZhiming Yang , and Hiroshi MiyamotoHiroshi Miyamoto View All Author Informationhttps://doi.org/10.1097/01.JU.0001008740.27639.cc.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: PPARγ coactivator-1 alpha (PGC1α), as a co-activator, is known to optimize the function of several transcription factors, including androgen receptor (AR). However, it remains unclear how PGC1α functions in prostate cancer, particularly via the pathways other than AR. Meanwhile, a bioinformatics search indicated that PGC1α could be a direct downstream target of lysine-specific demethylase 5B (KDM5B/PLU1/JARID1B). This study aimed to further determine how PGC1α induced prostate cancer outgrowth. METHODS: We immunohistochemically stained for PGC1α in a set of tissue microarray consisting of 225 radical prostatectomy (RP) specimens. We then assessed the effects of PGC1α silencing via its siRNA and a KDM5 inhibitor KDM5-C70 on the cell growth and expression of related proteins in prostate cancer lines. RESULTS: The levels of PGC1α expression were significantly higher in prostatic adenocarcinoma H-score (mean±SD): 166.4±105.6 than in normal tissue (19.2±30.8; p166) tumor had a significantly higher risk of biochemical recurrence after RP even in a multivariate setting (HR=5.225, p=0.009). In LNCaP/C4-2/CWR22Rv1 cells, PGC1α silencing resulted in considerable reduction in the expression of AR and prostate-specific antigen (PSA). Interestingly, PGC1α silencing inhibited the cell viability and migration of not only AR-positive lines but also AR-negative PC-3/DU145 lines. In addition, KDM5-C70 treatment considerably reduced PGC1α expression while showing inhibition in AR/PSA expression and cell viability/migration similar to PGC1α silencing. PGC1α silencing or KDM5-C70 treatment also down-regulated the expression of phospho-JAK2 and phospho-STAT3 in both AR-positive and AR-negative cells. Chromatin immunoprecipitation assay further revealed the binding of KDM5B to the promoter region of PGC1α in these lines. CONCLUSIONS: These findings suggest the involvement of PGC1α, as a downstream effector of KDM5B, in prostate cancer progression via both AR-dependent and AR-independent pathways. KDM5B-PGC1α is thus a potential therapeutic target for both androgen-sensitive and castration-resistant tumors. Meanwhile, PGC1α overexpression may serve as a useful prognosticator in those undergoing RP. Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e43 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Yuki Teramoto More articles by this author Zhiming Yang More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement PDF downloadLoading ...