RT Journal Article
SR Electronic
T1 KDM4A promotes NEPC progression through regulation of MYC expression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.14.491739
DO 10.1101/2022.05.14.491739
A1 Celia Sze Ling Mak
A1 Ming Zhu
A1 Xin Liang
A1 Feng Wang
A1 Anh G Hoang
A1 Xinzhi Song
A1 Peter Shepherd
A1 Derek Liang
A1 Jiwon Park
A1 Miao Zhang
A1 Eric Metzger
A1 Roland Schüle
A1 Abhinav K. Jain
A1 Min Gyu Lee
A1 Paul Corn
A1 Christopher J. Logothetis
A1 Ana Aparicio
A1 Nora Navone
A1 Patricia Troncoso
A1 Jianhua Zhang
A1 Sue-Hwa Lin
A1 Guocan Wang
YR 2022
UL http://biorxiv.org/content/early/2022/05/14/2022.05.14.491739.abstract
AB 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.