Albendazole in hydatid disease.

Abstract

<h3>ABSTRACT</h3> Despite advancement in treatment, prostate cancer (PCa) remains the second leading cause of death among men. Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of PCa and lacks life-prolonging treatment. Here we identified histone lysine demethylase KDM4A as a drive in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to adenocarcinoma. Also, we showed that knockdown or knockout of KDM4A in NEPC cell lines suppressed cancer cell growth <i>in vitro</i> and <i>in vivo</i>. Importantly, inactivation of <i>Kdm4a</i> in a genetically engineered mouse model of prostate cancer led to reduced tumor burden, reduced incidence of NEPC, and prolonged overall survival. Mechanistically, we found that <i>KDM4A</i> KD led to suppression of MYC signaling through direct transcriptional regulation of <i>MYC</i>. Importantly, MYC signaling is hyper-activated in human and mouse NEPC. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth <i>in vitro</i> and <i>in vivo</i>. Taken together, we demonstrated that KDM4A drives NEPC progression through regulation of MYC and targeting KDM4A can potentially be an effective therapeutic strategy for NEPC.