文章：

在癌症中被劫持：甲基转移酶KMT2 （MLL）家族

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

原文发布日期：2015-05-22

DOI: 10.1038/nrc3929

类型: Review Article

开放获取: 否

要点：

1. The histone–lysine N-methyltransferase (KMT2) family comprises a set of lysine methyltransferases that methylate the lysine 4 residue on histone H3 (H3K4). KMT2 family members demonstrate different substrate specificity in vitro and their methyltransferase activities are dependent, to varying degrees, on association with three core subunits (WD repeat protein 5, retinoblastoma binding protein 5 and ASH2L).
2. KMT2 family members have intrinsically different biochemical properties and are recruited to different genomic regions owing to their distinct domain structures and distinct interacting proteins.
3. KMT2 family members have important roles in transcription regulation. Among them, KMT2C and KMT2D are crucial for monomethylation of H3K4 at distal regulatory enhancers, whereas KMT2F and KMT2G are responsible for the majority of H3K4 trimethylation at transcription start sites.
4. There is extensive interplay between KMT2-dependent H3K4 methylation and DNA methylation, underlying the potential epigenetic stability of this histone methylation.
5. Mutations in the KMT2 family are among the most common genetic aberrations in human cancer — including haematological malignancies as well as solid tumours, such as large intestine, lung, endometrial, breast, bladder and brain cancers.
6. Mutations in the KMT2 family frequently involve the SET domain and the plant homeotic domains. Of somatic mutations in cancers with known zygosity, heterozygous mutations predominate. These features suggest that the wild-type KMT2 allele may be required for tumour survival, similar to KMT2A-rearranged mixed lineage leukaemia.
7. KMT2 family members may have distinct roles in cancer. Although it remains unclear whether cancer-derived KMT2 mutations are 'drivers' or 'passengers', mechanistic studies in animal models suggest that KMT2C may be a tumour suppressor and KMT2A and KMT2D may be proteins derived from proto-oncogenes.
8. The targeting of the fusion protein and wild-type KMT2A, as well as their interacting proteins, has emerged as a promising strategy to treat mixed lineage leukaemia, and may apply more broadly to a variety of cancers.

要点翻译：

1. 组蛋白-赖氨酸N-甲基转移酶（KMT2）家族包含一组对组蛋白H3第4位赖氨酸残基（H3K4）进行甲基化的赖氨酸甲基转移酶。KMT2家族成员在体外表现出不同的底物特异性，其甲基转移酶活性在不同程度上依赖于与三个核心亚基（WD重复蛋白5、视网膜母细胞瘤结合蛋白5和ASH2L）的结合。
2. KMT2家族成员具有本质不同的生化特性，并因其独特的结构域和相互作用蛋白而被招募至不同的基因组区域。
3. 该家族成员在转录调控中具有重要作用。其中，KMT2C和KMT2D对远端调控增强子处H3K4的单甲基化至关重要，而KMT2F和KMT2G则负责转录起始位点处大部分H3K4的三甲基化。
4. KMT2依赖的H3K4甲基化与DNA甲基化之间存在广泛相互作用，构成了这种组蛋白甲基化潜在表观遗传稳定性的基础。
5. KMT2家族突变是人类癌症中最常见的遗传异常之一，涉及血液系统恶性肿瘤以及实体肿瘤（如大肠癌、肺癌、子宫内膜癌、乳腺癌、膀胱癌和脑癌）。
6. KMT2家族突变常涉及SET结构域和植物同源结构域。在已知合子状态的癌症体细胞突变中，杂合突变占主导地位。这些特征表明野生型KMT2等位基因可能是肿瘤存活所必需的，这与KMT2A重排混合谱系白血病的情况相似。
7. KMT2家族成员在癌症中可能具有不同作用。虽然尚不清楚癌症来源的KMT2突变是“驱动者”还是“乘客”，但动物模型中的机制研究表明KMT2C可能是肿瘤抑制因子，而KMT2A和KMT2D可能源自原癌基因编码的蛋白质。
8. 靶向融合蛋白和野生型KMT2A及其相互作用蛋白，已成为治疗混合谱系白血病的有前景策略，并可能更广泛地应用于多种癌症类型。

英文摘要：

Histone–lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility. Although the human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member KMT2A in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.

摘要翻译： 

组蛋白-赖氨酸N-甲基转移酶2（KMT2）家族蛋白在基因组重要调控区域对组蛋白H3尾部的赖氨酸4进行甲基化，从而通过调节染色质结构和DNA可及性发挥关键功能。尽管人类KMT2家族最初因首个发现的成员KMT2A在该疾病中的作用而被命名为混合谱系白血病（MLL）家族，但最新的外显子测序研究显示，KMT2基因是多种人类癌症中最常突变的基因之一。将KMT2的分子机制与其在肿瘤发生中的作用相结合的努力，已促使第一代KMT2功能抑制剂的开发，这些抑制剂有望成为新型癌症疗法。

原文链接：

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases