School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 9RT, UK.
Cells. 2022 Mar 25;11(7):1113. doi: 10.3390/cells11071113.
Epigenetic regulation of gene expression is crucial to the determination of cell fate in development and differentiation, and the Polycomb (PcG) and Trithorax (TrxG) groups of proteins, acting antagonistically as complexes, play a major role in this regulation. Although originally identified in Drosophila, these complexes are conserved in evolution and the components are well defined in mammals. Each complex contains a protein with methylase activity (KMT), which can add methyl groups to a specific lysine in histone tails, histone 3 lysine 27 (H3K27), by PcG complexes, and H3K4 and H3K36 by TrxG complexes, creating transcriptionally repressive or active marks, respectively. Histone demethylases (KDMs), identified later, added a new dimension to histone methylation, and mutations or changes in levels of expression are seen in both methylases and demethylases and in components of the PcG and TrX complexes across a range of cancers. In this review, we focus on both methylases and demethylases governing the methylation state of the suppressive and active marks and consider their action and interaction in normal tissues and in cancer. A picture is emerging which indicates that the changes which occur in cancer during methylation of histone lysines can lead to repression of genes, including tumour suppressor genes, or to the activation of oncogenes. Methylases or demethylases, which are themselves tumour suppressors, are highly mutated. Novel targets for cancer therapy have been identified and a methylase (KMT6A/EZH2), which produces the repressive H3K27me3 mark, and a demethylase (KDM1A/LSD1), which demethylates the active H3K4me2 mark, are now under clinical evaluation.
基因表达的表观遗传调控对于发育和分化过程中细胞命运的决定至关重要，多梳（PcG）和三价（TrxG）蛋白复合物作为拮抗复合物，在这种调控中发挥着重要作用。虽然最初在果蝇中鉴定出这些复合物，但它们在进化中是保守的，并且在哺乳动物中，这些复合物的组成成分已经得到很好的定义。每个复合物都包含一个具有甲基转移酶活性（KMT）的蛋白质，它可以通过 PcG 复合物将甲基基团添加到组蛋白尾部的特定赖氨酸上，即组蛋白 3 赖氨酸 27（H3K27），通过 TrxG 复合物将 H3K4 和 H3K36 分别添加到转录抑制或激活标记上。后来鉴定出的组蛋白去甲基酶（KDM）为组蛋白甲基化增添了新的维度，在一系列癌症中，甲基转移酶和去甲基酶以及 PcG 和 TrX 复合物的组成成分都发生了突变或表达水平的变化。在这篇综述中，我们重点关注调控抑制性和激活性标记甲基化状态的甲基转移酶和去甲基酶，并考虑它们在正常组织和癌症中的作用和相互作用。一个正在出现的画面表明，在组蛋白赖氨酸甲基化过程中发生的癌症变化可能导致基因沉默，包括肿瘤抑制基因，或激活癌基因。作为肿瘤抑制因子的甲基转移酶或去甲基酶本身高度突变。已经确定了新的癌症治疗靶点，一种产生抑制性 H3K27me3 标记的甲基转移酶（KMT6A/EZH2）和一种去甲基化活性 H3K4me2 标记的去甲基酶（KDM1A/LSD1）目前正在临床评估中。
