Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer

Cancer Prev Res (Phila). 2020 Dec;13(12):979-988. doi: 10.1158/1940-6207.CAPR-20-0186. Epub 2020 Sep 11.

Abstract

Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems*
  • Cell Proliferation*
  • Cellular Senescence*
  • Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors*
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prostatic Intraepithelial Neoplasia / etiology
  • Prostatic Intraepithelial Neoplasia / metabolism
  • Prostatic Intraepithelial Neoplasia / pathology
  • Prostatic Intraepithelial Neoplasia / prevention & control*
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / prevention & control*

Substances

  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein