Simon Jeffrey A, Lange Carol A
Department of Genetics, University of Minnesota, Minneapolis, MN 55455, USA.
Mutat Res. 2008 Dec 1;647(1-2):21-9. doi: 10.1016/j.mrfmmm.2008.07.010. Epub 2008 Aug 3.
EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that targets lysine-27 of histone H3. This methylated H3-K27 chromatin mark is commonly associated with silencing of differentiation genes in organisms ranging from plants to flies to humans. Studies on human tumors show that EZH2 is frequently over-expressed in a wide variety of cancerous tissue types, including prostate and breast. Although the mechanistic contributions of EZH2 to cancer progression are not yet determined, functional links between EZH2-mediated histone methylation and DNA methylation suggest partnership with the gene silencing machinery implicated in tumor suppressor loss. Here we review the basic molecular biology of EZH2 and the findings that implicate EZH2 in different cancers. We also discuss EZH2 connections to other silencing enzymes, such as DNA methyltransferases and histone deacetylases, and we consider progress on deciphering mechanistic consequences of EZH2 overabundance and its potential roles in tumorigenesis. Finally, we review recent findings that link EZH2 roles in stem cells and cancer, and we consider prospects for integrating EZH2 blockade into strategies for developing epigenetic therapies.
EZH2是多梳抑制复合物2（PRC2）的催化亚基，PRC2是一种高度保守的组蛋白甲基转移酶，作用于组蛋白H3的赖氨酸-27。这种甲基化的H3-K27染色质标记通常与从植物到果蝇再到人类等生物体中分化基因的沉默有关。对人类肿瘤的研究表明，EZH2在包括前列腺癌和乳腺癌在内的多种癌组织类型中经常过度表达。尽管EZH2对癌症进展的机制贡献尚未确定，但EZH2介导的组蛋白甲基化与DNA甲基化之间的功能联系表明，它与涉及肿瘤抑制因子缺失的基因沉默机制存在协同作用。在此，我们综述了EZH2的基本分子生物学以及表明EZH2与不同癌症相关的研究发现。我们还讨论了EZH2与其他沉默酶（如DNA甲基转移酶和组蛋白脱乙酰酶）的联系，并考虑了在解读EZH2过量表达的机制后果及其在肿瘤发生中的潜在作用方面取得的进展。最后，我们综述了将EZH2在干细胞和癌症中的作用联系起来的最新研究发现，并考虑了将EZH2阻断纳入表观遗传治疗策略的前景。
