Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC

PLoS Biol. 2023 Apr 27;21(4):e3002038. doi: 10.1371/journal.pbio.3002038. eCollection 2023 Apr.


While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein / genetics
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylases
  • Histones* / metabolism
  • Humans
  • Male
  • Mice
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics


  • Enhancer of Zeste Homolog 2 Protein
  • EZH2 protein, human
  • Histones
  • Ezh2 protein, mouse
  • Histone Deacetylases