Christofides Anthos, Karantanos Theodoros, Bardhan Kankana, Boussiotis Vassiliki A
Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Oncotarget. 2016 Dec 20;7(51):85624-85640. doi: 10.18632/oncotarget.12928.
Polycomb group proteins regulate chromatin structure and have an important regulatory role on gene expression in various cell types. Two polycomb group complexes (Polycomb repressive complex 1 (PRC1) and 2 (PRC2)) have been identified in mammalian cells. Both PRC1 and PRC2 compact chromatin, and also catalyze histone modifications. PRC1 mediates monoubiquitination of histone H2A, whereas PRC2 catalyzes methylation of histone H3 on lysine 27. These alterations of histones can lead to altered gene expression patterns by regulating chromatin structure. Numerous studies have highlighted the role of the PRC2 catalytic component enhancer of zeste homolog 2 (EZH2) in neoplastic development and progression, and EZH2 mutations have been identified in various malignancies. Through modulating the expression of critical genes, EZH2 is actively involved in fundamental cellular processes such as cell cycle progression, cell proliferation, differentiation and apoptosis. In addition to cancer cells, EZH2 also has a decisive role in the differentiation and function of T effector and T regulatory cells. In this review we summarize the recent progress regarding the role of EZH2 in human malignancies, highlight the molecular mechanisms by which EZH2 aberrations promote the pathogenesis of cancer, and discuss the anti-tumor effects of EZH2 targeting via activating direct anti-cancer mechanisms and anti-tumor immunity.
多梳蛋白家族调控染色质结构，并在多种细胞类型的基因表达中发挥重要的调控作用。在哺乳动物细胞中已鉴定出两种多梳蛋白家族复合物（多梳抑制复合物1（PRC1）和2（PRC2））。PRC1和PRC2均能使染色质致密化，还能催化组蛋白修饰。PRC1介导组蛋白H2A的单泛素化，而PRC2催化组蛋白H3赖氨酸27位点的甲基化。这些组蛋白的改变可通过调节染色质结构导致基因表达模式的改变。大量研究强调了PRC2催化成分zeste同源物2增强子（EZH2）在肿瘤发生和进展中的作用，并且在多种恶性肿瘤中已鉴定出EZH2突变。通过调节关键基因的表达，EZH2积极参与细胞周期进程、细胞增殖、分化和凋亡等基本细胞过程。除癌细胞外，EZH2在T效应细胞和T调节细胞的分化及功能中也起决定性作用。在本综述中，我们总结了EZH2在人类恶性肿瘤中作用的最新进展，强调了EZH2异常促进癌症发病机制的分子机制，并讨论了通过激活直接抗癌机制和抗肿瘤免疫来靶向EZH2的抗肿瘤作用。
