%0 Journal Article %A Celia Sze Ling Mak %A Ming Zhu %A Xin Liang %A Feng Wang %A Anh G Hoang %A Xinzhi Song %A Peter Shepherd %A Derek Liang %A Jiwon Park %A Miao Zhang %A Eric Metzger %A Roland Schüle %A Abhinav K. Jain %A Min Gyu Lee %A Paul Corn %A Christopher J. Logothetis %A Ana Aparicio %A Nora Navone %A Patricia Troncoso %A Jianhua Zhang %A Sue-Hwa Lin %A Guocan Wang %T KDM4A promotes NEPC progression through regulation of MYC expression %D 2022 %R 10.1101/2022.05.14.491739 %J bioRxiv %P 2022.05.14.491739 %X 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 in vitro and in vivo. Importantly, inactivation of Kdm4a 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 KDM4A KD led to suppression of MYC signaling through direct transcriptional regulation of MYC. Importantly, MYC signaling is hyper-activated in human and mouse NEPC. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth in vitro and in vivo. 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.Competing Interest StatementConflict of interest: C. J. Logothetis reports receiving commercial research grants from Bayer, Sanofi, Janssen, Astellas Pharma, Pfizer; and honoraria from Bayer, Janssen, Sanofi, Astellas Pharma. No potential conflicts of interest were disclosed by the other authors. %U https://www.biorxiv.org/content/biorxiv/early/2022/05/14/2022.05.14.491739.full.pdf