Aberrations of EZH2 in Cancer
Aberrations of EZH2 in Cancer
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DOI：
10.1158/1078-0432.ccr-10-2156
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发表时间：
2011-05-01
影响因子：
11.5
通讯作者：
Cross, Nicholas C. P.
中科院分区：
文献类型：
--
作者：
Chase, Andrew;Cross, Nicholas C. P.
对基因表达的控制是在许多不同的水平上进行的，其中之一是基因及其控制元件对转录机制的可及性。可及性在很大程度上受染色质致密化程度的影响，而染色质致密化程度在一定程度上受到多梳状蛋白质的影响。EZH2与SUZ12和EED一起形成多梳抑制复合体2(PRC2)，它催化组蛋白H3赖氨酸27(H3K27me3)的三甲基化。PRC2可以招募其他多梳复合体、DNA甲基转移酶和组蛋白去乙酰基酶，导致关键发育位点上额外的转录抑制标记和染色质紧致。在许多实体肿瘤中，EZH2的过度表达是晚期和转移性疾病的标志，包括前列腺癌和乳腺癌。EZH2 Y641突变在淋巴瘤中被描述，并导致活性增强，而失活突变在预后不良的髓系肿瘤中被发现。目前还没有组蛋白去甲基化药物可用于治疗患者，但3-去氮杂环素(DZNep)可降低EZH2水平和H3K27三甲基化，导致乳腺和前列腺癌细胞体外增殖减少。此外，DNA脱甲基剂和组蛋白去乙酰化抑制剂的联合治疗也显示出协同效应，为未来精细化的表观遗传治疗开辟了可能性。临床癌症资源；17(9)；2613-8。(C)2011年AACR。
Control of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients, but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation, resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future. Clin Cancer Res; 17(9); 2613-8. (C)2011 AACR.