The combined effect of epigenetic inhibitors for LSD1 and BRD4 alters prostate cancer growth and invasion

Jianlin Wang, Qian Yu, Zhaoping Qiu, Tao Dai, Shuxia Wang, Xiuwei Yang, B. Mark Evers, Yadi Wu

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Epigenetic modifications play an important role in prostate tumor development and progression. Epigenetic drugs are emerging as effective modulators of gene expression that act on pathways potentially important in the control of cancer clinically. We investigated two different epigenetic modulating drugs, SP-2509 and JQ1, that target histone lysine demethylase 1 (LSD1), and bromodomain-containing protein (BRD), respectively and their combined effect in three different prostate cancer (PCa) types: 1) androgen receptor (AR)-positive and androgen-sensitive; 2) AR-positive but castration-resistant; and 3) androgen-nonresponsive. We found combined treatment provided a synergistic growth inhibition in castration-resistant PCa cells but knockdown of AR reduced sensitivity to both inhibitors in these cells. In the androgen-sensitive cell lines, AR knockdown attenuated sensitivity to the LSD1 inhibitor but not the JQ1 inhibitor. Strikingly, treatment with SP-2509 slightly, and JQ1 markedly increased invasion in PCa cells with high AR expression but decreased invasion in PCa cells with low/negative AR expression. Our results suggest that these two epigenetic drugs are novel and promising compounds for the development of PCa therapeutics, particularly for castration-resistant disease. However, due to the potential risks, including metastasis, caution must be exercised in the clinical setting.

Original languageEnglish
Pages (from-to)397-415
Number of pages19
JournalAging
Volume12
Issue number1
DOIs
StatePublished - Jan 15 2020

Bibliographical note

Funding Information:
We thank Dr. Cathy Anthony and Gilbreath Donna for critical reading and editing of this manuscript and Jingying Cao for technical help. We thank Dr. Huang for providing validated shAR and AR-expressing plasmid. Our research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). Our research was also supported by grants from American Cancer Society Research Scholar Award (RSG13187) and NIH (P20GM121327 and CA230758) to Y Wu.

Publisher Copyright:
© 2019 Wang et al.

Keywords

  • BRD4
  • Inhibitor
  • Invasion
  • LSD1
  • Prostate cancer

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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