Tiffen Jessamy, Gallagher Stuart J, Hersey Peter
Melanoma Research Group, Kolling Institute of Medical Research, University of Sydney, St Leonards, NSW, Australia.
Pigment Cell Melanoma Res. 2015 Jan;28(1):21-30. doi: 10.1111/pcmr.12280. Epub 2014 Jun 27.
Histone modifications are increasingly being recognized as important epigenetic mechanisms that govern chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), responsible for tri-methylation of lysine 27 on histone 3 (H3K27me3) that leads to gene silencing. This highly conserved histone methyltransferase is found to be overexpressed in many different types of cancers including melanoma, where it is postulated to abnormally repress tumor suppressor genes. Somatic mutations have been identified in approximately 3% of melanomas, and activating mutations described within the catalytic SET domain of EZH2 confer its oncogenic activity. In the following review, we discuss the evidence that EZH2 is an important driver of melanoma progression and we summarize the progress of EZH2 inhibitors against this promising therapeutic target.
组蛋白修饰日益被认为是调控染色质结构和基因表达的重要表观遗传机制。EZH2是多梳抑制复合物2（PRC2）的催化亚基，负责组蛋白3赖氨酸27的三甲基化（H3K27me3），从而导致基因沉默。这种高度保守的组蛋白甲基转移酶在包括黑色素瘤在内的许多不同类型癌症中均有过表达，据推测它会异常抑制肿瘤抑制基因。在大约3%的黑色素瘤中已发现体细胞突变，且在EZH2催化性SET结构域内描述的激活突变赋予了其致癌活性。在以下综述中，我们讨论了EZH2是黑色素瘤进展的重要驱动因素的证据，并总结了EZH2抑制剂针对这一有前景治疗靶点的研究进展。
