Cancer Res Treat.  2014 Jul;46(3):209-222.

Regulation and Role of EZH2 in Cancer

• Yamaguchi
• Hung MC

Abstract

Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.

Keyword

EZH2; PRC2; Neoplasms; Genetic transcription; Untranslated RNA; MicroRNAs; Post-translational protein processing

MeSH Terms

Drug Resistance
Epigenomics
Gene Silencing
Histones
Lysine
Methylation
MicroRNAs
Neoplasm Metastasis
Polycomb Repressive Complex 2
Protein Processing, Post-Translational
RNA, Untranslated
Transcription Factors
Transcription, Genetic
Histones
Lysine
MicroRNAs
Polycomb Repressive Complex 2
RNA, Untranslated
Transcription Factors

Figure

• 

  Fig. 1. Regulators of EZH2 expression and DNA targeting in cancer. EZH2 expression is regulated by various oncogenic transcription factors and tumor suppressor miRNAs. Access to the specific DNA sites is regulated by various transcription factors and noncoding RNAs (ncRNAs).

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  Fig. 2. Post-translational modifications of EZH2. EZH2 is phosphorylated at S21, T345, T372, T416, T487, Y641, and S734 by the indicated kinases. S75 is glycosylated by O-linked N-acetylglucosamine transferase (OGT). In addition, EZH2 is ubiquitinated by Smurf2, β-TrCP, and PRAJA1 and undergoes degradation.

• 

  Fig. 3. Various functions of EZH2 in human cancer. EZH2 silences multiple tumor suppressors such as INK4A/ARF and E-cadherin via canonical H3K27me3. EZH2 also methylates substrates other than H3K27, such as STAT3 and RORα. Furthermore, EZH2 has a methylase-independent function.

Reference

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