Going beyond Polycomb: EZH2 functions in prostate cancer

Su H. Park, Ka Wing Fong, Ezinne Mong, M. Cynthia Martin, Gary E. Schiltz, Jindan Yu*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

54 Scopus citations

Abstract

The Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) is one of the three core subunits of the Polycomb Repressive Complex 2 (PRC2). It harbors histone methyltransferase activity (MTase) that specifically catalyze histone 3 lysine 27 (H3K27) methylation on target gene promoters. As such, PRC2 are epigenetic silencers that play important roles in cellular identity and embryonic stem cell maintenance. In the past two decades, mounting evidence supports EZH2 mutations and/or over-expression in a wide array of hematological cancers and solid tumors, including prostate cancer. Further, EZH2 is among the most upregulated genes in neuroendocrine prostate cancers, which become abundant due to the clinical use of high-affinity androgen receptor pathway inhibitors. While numerous studies have reported epigenetic functions of EZH2 that inhibit tumor suppressor genes and promote tumorigenesis, discordance between EZH2 and H3K27 methylation has been reported. Further, enzymatic EZH2 inhibitors have shown limited efficacy in prostate cancer, warranting a more comprehensive understanding of EZH2 functions. Here we first review how canonical functions of EZH2 as a histone MTase are regulated and describe the various mechanisms of PRC2 recruitment to the chromatin. We further outline non-histone substrates of EZH2 and discuss post-translational modifications to EZH2 itself that may affect substrate preference. Lastly, we summarize non-canonical functions of EZH2, beyond its MTase activity and/or PRC2, as a transcriptional cofactor and discuss prospects of its therapeutic targeting in prostate cancer.

Original languageEnglish (US)
Pages (from-to)5788-5798
Number of pages11
JournalOncogene
Volume40
Issue number39
DOIs
StatePublished - Sep 30 2021

Funding

This work was supported in part by the NIH/NCI R01CA227918 (to JY), training grant T32CA09560 (to SP), prostate SPORE P50CA180995 (to JY), and Department of Defense grants W81XWH-17-1-0405 and W81XWH-17-1-0578 (to JY).

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Going beyond Polycomb: EZH2 functions in prostate cancer'. Together they form a unique fingerprint.

Cite this