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, 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 prostate cancer. 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 prostate cancer 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 CRPC cells. Collectively, these findings identify and characterize an MAOA-AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. SIGNIFICANCE: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.