Author:
Mak Celia Sze Ling,Zhu Ming,Liang Xin,Wang Feng,Yuan Fei,Hoang Anh G,Song Xinzhi,Shepherd Peter,Liang Derek,Suh Jessica,Pradhan Bijeta,Park Jiwon,Zhang Miao,Metzger Eric,Schule Roland,Jain Abhinav K.,Foster Barbara A.,Lee Min Gyu,Corn Paul,Logothetis Christopher J.,Aparicio Ana,Navone Nora,Troncoso Patricia,Tan Zhi,Zhang Jianhua,Lin Sue-Hwa,Wang Guocan
Abstract
Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer (PCa) and lacks life-prolonging treatment. The incidence of NEPC is increased due to the widespread use of AR pathway inhibitors (ARPIs) in the treatment of non-metastatic CRPC and hormone-sensitive metastatic tumors. Here, we identified histone lysine demethylase KDM4A as a key player in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Knockdown (KD) or knockout (KO) of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Mechanistically, we found that KDM4A promotes NEPC progression, in part, through direct transcriptional regulation of MYC. We showed that MYC is hyper-activated in human and mouse NEPC. KDM4A KD led to suppression of MYC signaling. MYC KD or inhibition profoundly suppressed NEPC cell proliferation. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth in vitro and in vivo. Taken together, we demonstrated that KDM4A is an important regulator of NEPC progression and targeting KDM4A may potentially be an effective therapeutic strategy for NEPC.
Publisher
Cold Spring Harbor Laboratory