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Going beyond Polycomb: EZH2 functions in prostate cancer

Oncogene volume 40, pages 5788–5798 (2021)Cite this article

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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.

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Fig. 1: Cooperation between PRC2 and other proteins regulates gene transcription.
Fig. 2: PRC2 directly methylates transcription factors to regulate their functions.
Fig. 3: Diverse roles of EZH2 in prostate cancer.

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Acknowledgements

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).

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  1. Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Su H. Park, Ka-Wing Fong, Ezinne Mong & Jindan Yu

  2. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA

    Ka-Wing Fong

  3. Department of Chemistry, Northwestern University, Evanston, IL, USA

    M. Cynthia Martin & Gary E. Schiltz

  4. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Gary E. Schiltz

  5. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

    Gary E. Schiltz & Jindan Yu

  6. Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Jindan Yu

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  1. Su H. Park
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SHP and JY wrote the manuscript. KF, EM, MCM, and GES read and edited the manuscript.

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Park, S.H., Fong, KW., Mong, E. et al. Going beyond Polycomb: EZH2 functions in prostate cancer. Oncogene 40, 5788–5798 (2021). https://doi.org/10.1038/s41388-021-01982-4

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