KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes

DUAN, LINGLING; RAI, GANESHA; ROGGERO, CARLOS M.; ZHANG, QING-JUN; WEI, QUN; MA, SHI HONG; ZHOU, YUNYUN; SANTOYO, JOHN; MARTINEZ, ELISABETH D.; XIAO, GUANGHUA; RAJ, GANESH V.; JADHAV, AJIT; SIMEONOV, ANTON; MALONEY, DAVID J.; RIZO, JOSEP; HSIEH, JER-TSONG; LIU, ZHI-PING

CHEMISTRY & BIOLOGY

CELL PRESS

Año: 2015 vol. 22 p. 1185 - 1196

1074-5521

Histone lysine demethylase KDM4/JMJD2s are overexpressedin many human tumors including prostatecancer (PCa). KDM4s are co-activators of androgenreceptor (AR) and are thus potential therapeutic targets.Yet to date few KDM4 inhibitors that haveanti-prostate tumor activity in vivo have been developed.Here, we report the anti-tumor growth effectand molecular mechanisms of three novel KDM4 inhibitors(A1, I9, and B3). These inhibitors repressedthe transcription of both AR and BMYB-regulatedgenes. Compound B3 is highly selective for a varietyof cancer cell lines including PC3 cells that lack AR.B3 inhibited the in vivo growth of tumors derivedfrom PC3 cells and ex vivo human PCa explants.We identified a novel mechanism by which KDM4Bactivates the transcription of Polo-like kinase 1(PLK1). B3 blocked the binding of KDM4B to thePLK1 promoter. Our studies suggest a potentialmechanism-based therapeutic strategy for PCa andtumors with elevated KDM4B/PLK1 expression.