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Review
. 2016 Jun 2;17(6):579-91.
doi: 10.1080/15384047.2016.1167291. Epub 2016 Apr 22.

Role of EZH2 histone methyltrasferase in melanoma progression and metastasis

Affiliations
Review

Role of EZH2 histone methyltrasferase in melanoma progression and metastasis

Fade Mahmoud et al. Cancer Biol Ther. .

Abstract

There is accumulating evidence that the histone methyltransferase enhancer of zeste homolog 2 (EZH2), the main component of the polycomb-repressive complex 2 (PRC2), is involved in melanoma progression and metastasis. Novel drugs that target and reverse such epigenetic changes may find a way into the management of patients with advanced melanoma. We provide a comprehensive up-to-date review of the role and biology of EZH2 on gene transcription, senescence/apoptosis, melanoma microenvironment, melanocyte stem cells, the immune system, and micro RNA. Furthermore, we discuss EZH2 inhibitors as potential anti-cancer therapy.

Keywords: Chromatin; EZH2; H3K27 trimethylation; epigenetic changes; histone; melanoma; polycomb-repressive complex.

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Figures

Figure 1.
Figure 1.
The PRC2 complex and histone methylation; (A) If the lysine amino acid 27 on histone 3 is pre-acetylated, the histone deacetylase (HDAC) enzyme will remove the acetyl group from an N-acetyl lysine amino acid first; (B) EZH2 (one of the 5 subunits of PCR2 complex) adds methyl groups to Histone 3 at Lysine 27. Triple methylation of H3K27 (H3K273m) leads to transcription repression and silencing of genes; (C) DNA methyltransferases (DNMT) add a methyl group to cytosines within CG dinucleotides or CNG trinucleotides (N can be C, A, G or T) in CpG islands leading to transcriptional repression. Ac: acetylation; M: methylation; CG: cytosine-guanine.
Figure. 2
Figure. 2
Biology of EZH2 overexpression in melanoma The Immune system: EZH2 overexpression has a positive effect on the immune system by enhancing the function of both B and T cells, however, it has a negative effect by suppressing MHC II expression and hence help melanoma cells escape immune surveillance; Gene transcription: EZH2 silences tumor suppressor genes; Senescence and apoptosis: EZH2 silences apoptotic genes and helps melanoma cells escape senescence; CdKI: EZH2-mediated silencing of cyclin-dependent kinase inhibitors (CdkI), also called INK4 proteins, results in inhibition of apoptosis and senescence and stimulation of melanoma cell proliferation; Cell differentiation: EZH2 enhance the process of de-differentiation to neural-like stem cells; Epithelial-Mesenchymal Transition (EMT) and Microenvironment: EZH2 regulates the EMT and causes morphologic changes in melanocytes (increased motility, branching, aggressive growth, and cell migration) that help shape the interactions between melanoma cells and the microenvironment.
Figure 3.
Figure 3.
Regulation of EZH2 expression: E2F: is a group of genes that codifies a family of transcriptional factors in higher eukaryotes, cMyc is a regulatory gene that codes for a transcriptional factor, MEK-ERK is a pathway also known as the Ras-Raf-MEK-ERK pathway, BRAF is a human gene that makes a protein called B-Raf, CdK1 and 2: Cyclin dependent kinases 1 and 2, pRB: phosphorylated retinoblastoma gene, p16INK4B is a tumor suppressor gene, miRNA: micro RNA, SSX2: synovial sarcoma X gene.

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