Glutamate Decarboxylase 65 Signals through the Androgen Receptor to Promote Castration Resistance in Prostate Cancer.

The transition from an androgen-dependent to a castration-resistant state is a critical event in the progression of prostate cancer. In this study, we compared metabolic pathways between isogenic human androgen-dependent and castration-resistant prostate cancer (CRPC) patient-derived xenograft models, and found consistent activation of the γ-aminobutyric acid (GABA) shunt in CRPC. This difference was the result of phosphorylation and activation of glutamate decarboxylase 65 (GAD65), which synthesizes GABA from glutamate by decarboxylation. Mechanistic investigation showed that GABA binds to and retains the androgen receptor (AR) in the nucleus by facilitating AR association with the nuclear zinc finger protein ZNHIT3. GAD65 knockdown decreased the growth of multiple established CRPC xenografts and markedly delayed the time to emergence of castration resistance. These data encourage exploring GAD65 as a therapeutic target for CRPC. SIGNIFICANCE: This study reports metabolic alterations that could be responsible for the development of CRPC and identifies the GABA-producing enzyme GAD65 as a potential new therapeutic target.See related commentary by Taylor and Watt, p. 4580. ©2019 American Association for Cancer Research.