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 γ (ERRγ) 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 ERRγ. This metabolic state paralleled the loss of ERRγ 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 ERRγ expression and disease severity. These results illuminate a mechanism in which androgen-dependent repression of ERRγ reprograms prostate cancer cell metabolism to favor mitochondrial activity and cell proliferation. Furthermore, they rationalize strategies to reactivate ERRγ signaling as a generalized therapeutic approach to manage prostate cancer. Cancer Res; 77(2); 378-89. ©2016 AACR.