文章：

共价组蛋白修饰——人类癌症中的错误书写、错误解读和错误清除

Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers

原文发布日期：2010-07-01

DOI: 10.1038/nrc2876

类型: Review Article

开放获取: 否

要点：

1. Post-translational modifications of histones introduce meaningful variations into chromatin and provide a regulatory platform for controlling and/or fine-tuning many important DNA-templated processes, including gene transcription, the repair of DNA damage and DNA replication.
2. Histone modifications, together with factors responsible for adding ('writing'), interpreting ('reading') and removing ('erasing') histone modifications, regulate specific and distinct functional outputs of our genomes, which constitute the basis of the 'histone code hypothesis'.
3. As recent evidence starts to link the miswriting, misinterpretation and mis-erasing of histone modifications to oncogenesis, we further propose that misregulation of the histone code leads to deregulated gene expression and perturbation of cellular identity, and is therefore a major contributor to cancer initiation, progression and/or metastasis.
4. Mixed lineage leukaemia (MLL) and enhancer of zeste 2 (EZH2) catalyse the addition of methylation of histone H3 lysine 4 (H3K4) and H3 lysine 27 (H3K27), respectively, which are arguably two of the most important histone methylation marks. MLL rearrangement and deregulation of EZH2 are among the most common mutations in leukaemia and solid tumours, respectively.
5. Several plant homoedomain (PHD) finger-containing proteins have recently been identified as reading factors of trimethylation of H3K4 (H3K4me3). Misinterpretation of H3K4me3 by leukaemia-associated translocations of PHD finger factors (NUP98–JARID1A or NUP98–PHF23) is crucial for the induction of myeloid leukaemia; somatic mutations of ING1, a PHD finger factor, interfere with the reading of H3K4me3 and associate with the development of oesophageal squamous cell carcinoma, head and neck squamous cell carcinoma and melanoma.
6. Deregulation or mutations of the recently identified H3K4- or H3K27-specific histone demethylases have been observed in solid tumours. However, their involvement in cancer development and underlying mechanisms are largely unclear.

要点翻译：

1. 组蛋白的翻译后修饰为染色质引入了有意义的变异，并为控制和/或微调许多重要的DNA模板化过程（包括基因转录、DNA损伤修复和DNA复制）提供了一个调控平台。
2. 组蛋白修饰，连同负责添加（“写入”）、解读（“读取”）和移除（“擦除”）组蛋白修饰的因子，调控着我们基因组特定而独特的功能输出，这构成了“组蛋白密码假说”的基础。
3. 随着近期证据开始将组蛋白修饰的错误写入、错误解读和错误擦除与肿瘤发生联系起来，我们进一步提出，组蛋白密码的调控异常会导致基因表达失调和细胞身份扰乱，因此是癌症发生、进展和/或转移的一个主要贡献者。
4. 混合谱系白血病（MLL）和zeste 2增强子（EZH2）分别催化组蛋白H3赖氨酸4（H3K4）和H3赖氨酸27（H3K27）的甲基化添加，这可以说是两个最重要的组蛋白甲基化标记。MLL重排和EZH2的调控失常分别是白血病和实体瘤中最常见的突变之一。
5. 最近已鉴定出几种含有植物同源结构域（PHD）指结构的蛋白作为H3K4三甲基化（H3K4me3）的读取因子。在白血病中，与PHD指因子易位（NUP98–JARID1A或NUP98–PHF23）相关的H3K4me3错误解读对于诱导髓系白血病至关重要；ING1（一种PHD指因子）的体细胞突变干扰了H3K4me3的读取，并与食管鳞状细胞癌、头颈部鳞状细胞癌和黑色素瘤的发展相关。
6. 在实体瘤中已观察到近期发现的H3K4或H3K27特异性组蛋白去甲基化酶的调控失常或突变。然而，它们在癌症发展中的参与及其潜在机制在很大程度上尚不清楚。

英文摘要：

Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the deregulation of factors that mediate the modification installation, removal and/or interpretation, actively contributes to human cancer. In this Review, we summarize recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins, and how misreading, miswriting and mis-erasing of histone methylation marks can be associated with oncogenesis and progression. These observations provide us with a greater mechanistic understanding of epigenetic alterations in human cancers and might also help direct new therapeutic interventions in the future.

摘要翻译： 

组蛋白的翻译后修饰为基因转录和DNA损伤修复等过程提供了重要的调控平台。越来越明确的是，组蛋白修饰的失调——由介导修饰的建立、去除和/或解读因子的异常调控引起——会积极推动人类癌症的发生。在本综述中，我们总结了关于含植物同源结构域指蛋白对某些组蛋白甲基化解读的最新进展，以及组蛋白甲基化标记的误读、误写和误擦如何与肿瘤发生和进展相关。这些观察使我们对人类癌症中的表观遗传改变有了更深入机制性理解，也可能为未来新的治疗干预提供方向。

原文链接：

Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers