Abstract
PPARγ coactivator-1α (PGC1α), as a co-activator, is known to optimize the action of several transcription factors, including androgen receptor (AR). However, the precise functions of PGC1α in prostate cancer, particularly those via the non-AR pathways, remain poorly understood. Meanwhile, our bioinformatics search suggested that PGC1α could be a direct downstream target of lysine-specific demethylase 5B (KDM5B/JARID1B/PLU1). We herein aimed to investigate how PGC1α induced prostate cancer outgrowth. Immunohistochemistry in radical prostatectomy specimens showed that the levels of PGC1α expression were significantly higher in prostatic adenocarcinoma [H-score (mean ± SD): 179.0 ± 111.6] than in adjacent normal-appearing tissue (16.7 ± 29.9, P<0.001) or high-grade prostatic intraepithelial neoplasia (79.0 ± 94.7, P<0.001). Although there were no strong associations of PGC1α expression with tumor grade or stage, outcome analysis revealed that patients with high PGC1α (H-score of ≥200) tumor had a significantly higher risk of postoperative biochemical recurrence even in a multivariable setting (hazard ratio 5.469, P=0.004). In prostate cancer LNCaP and C4-2 cells, PGC1α silencing resulted in considerable reduction in the levels of prostate-specific antigen expression. Interestingly, PGC1α silencing inhibited the cell viability of not only AR-positive LNCaP/C4-2/22Rv1 lines but also AR-negative PC3/DU145 lines. Chromatin immunoprecipitation assay further revealed the binding of KDM5B to the promoter region of PGC1α in these lines. Additionally, treatment with a KDM5 inhibitor KDM5-C70 considerably reduced the expression of PGC1α and prostate-specific antigen, as well as the cell viability of all the AR-positive and AR-negative lines examined. 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. 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 radical prostatectomy.