Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4-2Oh2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats
Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4-2Oh2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats
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DOI：
10.1093/carcin/bgi364
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发表时间：
2006-06-01
期刊：
影响因子：
4.7
通讯作者：
Karpinets, Tatiana V.
中科院分区：
文献类型：
--
作者：
Pogribny, Igor P.;Ross, Sharon A.;Karpinets, Tatiana V.
近年来，癌症表观遗传学领域受到了广泛关注。然而，癌症表观遗传学与癌症病因学的关系尚不清楚。最近的研究表明，改变DNA甲基化和组蛋白修饰的参与，在肿瘤发展的癌前阶段的表观遗传重编程细胞与特定的肿瘤相关的表型的出现。在这项研究中，我们使用了一个甲基缺乏模型的啮齿动物肝癌的致癌过程中，DNA，组蛋白H3赖氨酸9和组蛋白H4赖氨酸20甲基化的作用，和表达水平的Suv 39 h1和Suv 4 - 2 Oh 2组蛋白甲基转移酶。我们证明，肝肿瘤的发展的特点是进行性去甲基化的DNA重复序列，减少组蛋白H4赖氨酸20三甲基化，和Suv 4 - 2 OH 2组蛋白甲基转移酶的表达逐渐减少。在癌前结节和肝肿瘤中观察到组蛋白H3赖氨酸9的三甲基化和Suv 39 h1组蛋白甲基转移酶的表达显著增加，表明这些表观遗传改变在癌变后期的促进作用。肿瘤特异性表观遗传学改变（重复元件的去甲基化，组蛋白H4赖氨酸20三甲基化的损失，Suv 4 - 2 Oh 2和Suv 39 h1组蛋白甲基转移酶的表达改变）在肝癌发生的癌前阶段的出现为肿瘤发生的表观遗传学假说提供了实验支持，该假说认为应激诱导的细胞表观遗传重编程是成功突变的重要前提。
The field of cancer epigenetics has received much attention in recent years. However, the relationship of cancer epigenetics with cancer etiology is not clear. Recent studies suggest the involvement of altered DNA methylation and histone modifications in the emergence of epigenetically reprogrammed cells with specific tumor-related phenotypes at premalignant stages of tumor development. In this study, we used a methyl-deficient model of rodent hepatocarcinogenesis to examine the roles of DNA, histone H3 lysine 9 and histone H4 lysine 20 methylation, and the level of the expression of Suv39h1 and Suv4-2Oh2 histone methyltransferases in the carcinogenic process. We demonstrated that the development of liver tumors was characterized by progressive demethylation of DNA repeats, decrease in histone H4 lysine 20 trimethylation, and a gradual decrease in the expression of Suv4-2Oh2 histone methyltransferase. A prominent increase in the trimethylation of histone H3 lysine 9 and in the expression of Suv39h1 histone methyltransferase was observed in preneoplastic nodules and liver tumors indicating the promotional role of these epigenetic alterations at later stages of carcinogenesis. The appearance of tumor-specific epigenetic alterations (demethylation of repetitive elements, loss of histone H4 lysine 20 trimethylation, altered expression of Suv4-2Oh2 and Suv39h1 histone methyltransferases) at preneoplastic stages of hepatocarcinogenesis provides experimental support for the epigenetic hypothesis of tumorigenesis that considers stress-induced epigenetic reprogramming of the cell as an important prerequisite to succeeding mutations.