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

Lingling Duan, Ganesha Rai, Carlos Roggero, Qing Jun Zhang, Qun Wei, Shi Hong Ma, Yunyun Zhou, John Santoyo, Elisabeth D Martinez, Guanghua Xiao, Ganesh Raj, Ajit Jadhav, Anton Simeonov, David J. Maloney, Jose Rizo-Rey, Jer-Tsong Hsieh, Zhi-Ping Liu

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Summary Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of Polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggest a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.

Original languageEnglish (US)
Pages (from-to)1185-1196
Number of pages12
JournalChemistry and Biology
Volume22
Issue number9
DOIs
Publication statusPublished - Apr 11 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

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