Gall Trošelj Koraljka, Novak Kujundzic Renata, Ugarkovic Djurdjica
Division of Molecular Medicine, Laboratory for Epigenomics, Rudjer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia.
Division of Molecular Biology, Laboratory for Evolutionary Genetics, Rudjer Boskovic Institute, Bijenicka cesta 54, 10 000 Zagreb, Croatia.
Clin Epigenetics. 2016 May 27;8:55. doi: 10.1186/s13148-016-0226-1. eCollection 2016.
When assembled in multiprotein polycomb repressive complexes (PRCs), highly evolutionary conserved polycomb group (PcG) proteins epigenetically control gene activity. Although the composition of PRCs may vary considerably, it is well established that the embryonic ectoderm development (EED) 1, suppressor of zeste (SUZ) 12, and methyltransferase enhancer of zeste (EZH2)-containing complex, PRC2, which is abundant in highly proliferative cells (including cancer cells), establishes a repressive methylation mark on histone 3 (H3K27me3). From the perspective of molecular cancer pathogenesis, this effect, when directed towards a promoter of tumor suppressor genes, represents pro-tumorigenic effect. This mode of action was shown in several cancer models. However, EZH2 function extends beyond this scenario. The highly specific cellular background, related to the origin of cell and numerous external stimuli during a given time-window, may be the trigger for EZH2 interaction with other proteins, not necessarily histones. This is particularly relevant for cancer. This review provides a critical overview of the evolutional importance of PRC and discusses several important aspects of EZH2 functioning within PRC. The review also deals with mutational studies on EZH2. Due to the existence of several protein (and messenger RNA (mRNA)) isoforms, these mutations were stratified, using the protein sequence which is considered canonical. This approach showed that there is an urgent need for the uniformed positioning of currently known EZH2 mutations (somatic-in tumors, as well as germline mutations in the Weaver's syndrome). Finally, we discuss EZH2 function with respect to amount of trimethylated H3K27, in a specific cellular milieu, through presenting the most recent data related to EZH2-H3K27m3 relationship in cancer. All these points are significant in considering EZH2 as a therapeutic target.
当组装成多蛋白多梳抑制复合物（PRC）时，高度进化保守的多梳蛋白家族（PcG）蛋白可通过表观遗传方式控制基因活性。尽管PRC的组成可能有很大差异，但已明确的是，在高增殖细胞（包括癌细胞）中大量存在的包含胚胎外胚层发育蛋白（EED）1、zeste基因抑制因子（SUZ）12和zeste基因增强子甲基转移酶（EZH2）的复合物PRC2，会在组蛋白3（H3K27me3）上建立抑制性甲基化标记。从分子癌症发病机制的角度来看，当这种作用针对肿瘤抑制基因的启动子时，就代表了促肿瘤作用。这种作用模式已在多种癌症模型中得到证实。然而，EZH2的功能并不局限于此。与细胞起源相关的高度特异性细胞背景以及给定时间窗口内的众多外部刺激，可能是EZH2与其他蛋白（不一定是组蛋白）相互作用的触发因素。这在癌症中尤为重要。本综述对PRC的进化重要性进行了批判性概述，并讨论了EZH2在PRC中发挥功能的几个重要方面。该综述还涉及EZH2的突变研究。由于存在几种蛋白质（和信使核糖核酸（mRNA））异构体，这些突变根据被视为规范的蛋白质序列进行了分层。这种方法表明，迫切需要对目前已知的EZH2突变（肿瘤中的体细胞突变以及韦弗综合征中的种系突变）进行统一定位。最后，我们通过展示与癌症中EZH2 - H3K27m3关系相关的最新数据，讨论了在特定细胞环境中EZH2功能与三甲基化H3K27量的关系。在将EZH2视为治疗靶点时，所有这些要点都具有重要意义。
