Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer

How androgen signaling contributes to the oncometabolic state of prostate cancer remains unclear. Here, we show how the estrogen-related receptor gamma (ERR gamma) negatively controls mitochondrial respiration in prostate cancer cells. Sustained treatment of prostate cancer cells with androgens increased the activity of several metabolic pathways, including aerobic glycolysis, mitochondrial respiration, and lipid synthesis. An analysis of the intersection of gene expression, binding events, and motif analyses after androgen exposure identified a metabolic gene expression signature associated with the action of ERR gamma. This metabolic state paralleled the loss of ERR gamma expression. It occurred in both androgen-dependent and castration-resistant prostate cancer and was associated with cell proliferation. Clinically, we observed an inverse relationship between ERR gamma expression and disease severity. These results illuminate a mechanism in which and rogendependent repression of ERR gamma reprograms prostate cancer cell metabolism to favor mitochondrial activity and cell proliferation. Furthermore, they rationalize strategies to reactivate ERR gamma signaling as a generalized therapeutic approach to manage prostate cancer. (C) 2016 AACR.