Therapeutic targeting of histone lysine demethylase KDM4B blocks the growth of castration-resistant prostate cancer

Lingling Duan, Yu An Chen, Yanping Liang, Zhenhua Chen, Jun Lu, Yong Fang, Jiazheng Cao, Jian Lu, Hongwei Zhao, Rey Chen Pong, Elizabeth Hernandez, Payal Kapur, Tram Anh T. Tran, Tristan Smith, Elisabeth D. Martinez, Jung Mo Ahn, Jer Tsong Hsieh, Jun hang Luo, Zhi Ping Liu

Research output: Contribution to journalArticlepeer-review


Epigenetics is an emerging mechanism for tumorigenesis. Treatment that targets epigenetic regulators is becoming an attractive strategy for cancer therapy. The role of epigenetic therapy in prostate cancer (PCa) remains elusive. Previously we demonstrated that upregulation of histone lysine demethylase KDM4B correlated with the appearance of castration resistant prostate cancer (CRPC) and identified a small molecular inhibitor of KDM4B, B3. In this study, we further investigated the role of KDM4B in promoting PCa progression and tested the efficacy of B3 using clinically relevant PCa models including PCa cell line LNCaP and 22Rv1 and xenografts derived from these cell lines. In loss and gain-functional studies of KDM4B in PCa cells, we found that overexpression of KDM4B in LNCaP cells enhanced its tumorigenicity whereas knockdown of KDM4B in 22Rv1 cells reduced tumor growth in castrated mice. B3 suppressed the growth of 22Rv1 xenografts and sensitized tumor to anti-androgen receptor (AR) antagonist enzalutamide inhibition. B3 also inhibited 22Rv1 tumor growth synergistically with rapamycin, leading to cell apoptosis. Comparative transcriptomic analysis performed on KDM4B knockdown and B3-treated 22Rv1 cells revealed that B3 inhibited both H3K9me3 and H3K27me3 demethylase activities. Our studies establish KDM4B as a target for CRPC and B3 as a potential therapeutic agent. B3 as monotherapy or in combination with other anti-PCa therapeutics offers proof of principle for the clinical translation of epigenetic therapy targeting KDMs for CRPC patients.

Original languageEnglish (US)
Article number114077
JournalBiomedicine and Pharmacotherapy
StatePublished - Feb 2023
Externally publishedYes


  • Castration-resistant prostate cancer
  • Histone lysine demethylase
  • KDM inhibitor
  • KDM4B
  • Prostate cancer therapy

ASJC Scopus subject areas

  • Pharmacology


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