文章：

非组蛋白赖氨酸甲基化在人类肿瘤发生中的关键作用

Critical roles of non-histone protein lysine methylation in human tumorigenesis

原文发布日期：2015-01-23

DOI: 10.1038/nrc3884

类型: Review Article

开放获取: 否

要点：

1. Lysine methylation is widely recognized as a fundamental post-translational modification.
2. Most protein lysine methyltransferases (PKMTs) contain the SET domain, but several non-SET proteins such as DOT1-like histone H3 lysine 79 methyltransferase (DOT1L), methyltransferase-like 10 (METTL10) and METTL21A are also known to have lysine N-methyltransferase activity.
3. Protein lysine demethylases (PKDMs) consist of the lysine-specific demethylase 1 (LSD1) family, which are flavin-dependent monoamine oxidases, and the Jumonji C (JmjC) domain-containing proteins, which are α-ketoglutarate-dependent Fe(ii) dioxygenases.
4. The biological importance of protein lysine methylation in cancer can be categorized into five different functions: effect on other protein modifications; protein–protein interactions; protein stability; subcellular localization; and promoter binding.
5. Although the most widely recognized function of PKMTs and PKDMs in cancer is their effects on histones and epigenetic regulation, nearly 20 non-histone proteins related to human cancer, including p53 and RB1, have also been discovered to be methylated at lysine residues.
6. Somatic mutations of PKMTs and PKDMs are frequently found in human cancer, and it is possible that they may affect the methylation of non-histone substrates.
7. Inhibitors targeting PKMTs and PKDMs are considered to be promising agents for anticancer therapy, and it is important that a thorough understanding of all of the substrates of these enzymes is made to discern the precise mechanism of action of these inhibitors.

要点翻译：

1. 赖氨酸甲基化被广泛认为是一种基本的翻译后修饰。
2. 大多数蛋白质赖氨酸甲基转移酶（PKMTs）含有SET结构域，但一些非SET蛋白，如DOT1样组蛋白H3赖氨酸79甲基转移酶（DOT1L）、甲基转移酶样10（METTL10）和METTL21A，也被发现具有赖氨酸N-甲基转移酶活性。
3. 蛋白质赖氨酸去甲基酶（PKDMs）包括赖氨酸特异性去甲基酶1（LSD1）家族（依赖黄素的单胺氧化酶）和含有Jumonji C（JmjC）结构域的蛋白质（依赖α-酮戊二酸的Fe(II)双加氧酶）。
4. 蛋白质赖氨酸甲基化在癌症中的生物学重要性可分为五个不同功能：影响其他蛋白质修饰；蛋白质-蛋白质相互作用；蛋白质稳定性；亚细胞定位；以及启动子结合。
5. 尽管PKMTs和PKDMs在癌症中最广为人知的功能是对组蛋白和表观遗传调控的影响，但已发现近20种与人类癌症相关的非组蛋白（包括p53和RB1）也在赖氨酸残基上发生甲基化。
6. PKMTs和PKDMs的体细胞突变在人类癌症中常见，这些突变可能影响非组蛋白底物的甲基化。
7. 针对PKMTs和PKDMs的抑制剂被认为是抗癌治疗的有前景的药物，重要的是要全面了解这些酶的所有底物，以辨别这些抑制剂的确切作用机制。

英文摘要：

Several protein lysine methyltransferases and demethylases have been identified to have critical roles in histone modification. A large body of evidence has indicated that their dysregulation is involved in the development and progression of various diseases, including cancer, and these enzymes are now considered to be potential therapeutic targets. Although most studies have focused on histone methylation, many reports have revealed that these enzymes also regulate the methylation dynamics of non-histone proteins such as p53, RB1 and STAT3 (signal transducer and activator of transcription 3), which have important roles in human tumorigenesis. In this Review, we summarize the molecular functions of protein lysine methylation and its involvement in human cancer, with a particular focus on lysine methylation of non-histone proteins.

摘要翻译： 

多种蛋白质赖氨酸甲基转移酶和去甲基化酶已被证实在组蛋白修饰中发挥关键作用。大量证据表明，这些酶的失调与包括癌症在内的多种疾病的发生和发展密切相关，因此它们现被视为潜在的治疗靶点。尽管大多数研究集中于组蛋白甲基化，但许多报道揭示，这些酶同样调控非组蛋白（如p53、RB1和STAT3（信号转导与转录激活因子3））的甲基化动态，而这些蛋白在人类肿瘤发生中具有重要作用。在本综述中，我们总结了蛋白质赖氨酸甲基化的分子功能及其在人类癌症中的作用，特别聚焦于非组蛋白的赖氨酸甲基化。

原文链接：

Critical roles of non-histone protein lysine methylation in human tumorigenesis