KDM4A promotes NEPC progression through regulation of MYC expression.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a promising therapeutic target, as knockdown or knockout of KDM4A suppresses NEPC cell proliferation in vitro and tumor growth in vivo. Mechanistically, we found that KDM4A directly regulates the transcription of the oncogene MYC, which we show is essential for NEPC cell growth through knockdown and inhibitor studies. Importantly, pharmacologic inhibition of KDM4A using QC6352, a potent pan-KDM4 inhibitor, significantly reduced NEPC cell proliferation in vitro and tumor growth in vivo, providing proof-of-concept for therapeutic targeting. Collectively, our findings establish KDM4A as a critical epigenetic driver of NEPC through MYC regulation and demonstrate its therapeutic potential for this lethal disease that currently lacks effective treatments.