Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer.

Androgen receptor (AR) is the primary oncogenic driver of prostate cancer (PC), including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in PC. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1-AR interactions. Silencing MAOA suppressed AR-mediated PC development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and castration-resistant PC cells. Collectively, these findings identify and characterize a MAOA-AR reciprocal regulatory circuit with coamplified effects in PC. Moreover, they suggest that co-targeting this complex may be a viable therapeutic strategy to treat PC and CRPC.