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Going beyond Polycomb: EZH2 Functions in Prostate Cancer

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 suc...

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Autores principales: Park, Su H., Fong, Ka-Wing, Mong, Ezinne, Martin, M. Cynthia, Schiltz, Gary E., Yu, Jindan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487936/
https://www.ncbi.nlm.nih.gov/pubmed/34349243
http://dx.doi.org/10.1038/s41388-021-01982-4
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author Park, Su H.
Fong, Ka-Wing
Mong, Ezinne
Martin, M. Cynthia
Schiltz, Gary E.
Yu, Jindan
author_facet Park, Su H.
Fong, Ka-Wing
Mong, Ezinne
Martin, M. Cynthia
Schiltz, Gary E.
Yu, Jindan
author_sort Park, Su H.
collection PubMed
description 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 up-regulated 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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spelling pubmed-84879362022-02-04 Going beyond Polycomb: EZH2 Functions in Prostate Cancer Park, Su H. Fong, Ka-Wing Mong, Ezinne Martin, M. Cynthia Schiltz, Gary E. Yu, Jindan Oncogene Article 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 up-regulated 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. 2021-08-04 2021-09 /pmc/articles/PMC8487936/ /pubmed/34349243 http://dx.doi.org/10.1038/s41388-021-01982-4 Text en https://www.springernature.com/gp/open-research/policies/accepted-manuscript-termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
spellingShingle Article
Park, Su H.
Fong, Ka-Wing
Mong, Ezinne
Martin, M. Cynthia
Schiltz, Gary E.
Yu, Jindan
Going beyond Polycomb: EZH2 Functions in Prostate Cancer
title Going beyond Polycomb: EZH2 Functions in Prostate Cancer
title_full Going beyond Polycomb: EZH2 Functions in Prostate Cancer
title_fullStr Going beyond Polycomb: EZH2 Functions in Prostate Cancer
title_full_unstemmed Going beyond Polycomb: EZH2 Functions in Prostate Cancer
title_short Going beyond Polycomb: EZH2 Functions in Prostate Cancer
title_sort going beyond polycomb: ezh2 functions in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487936/
https://www.ncbi.nlm.nih.gov/pubmed/34349243
http://dx.doi.org/10.1038/s41388-021-01982-4
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