Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins
Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins
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DOI：
10.4161/cbt.5.1.2288
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发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Pogribny, IP
中科院分区：
文献类型：
--
作者：
Tryndyak, VP;Kovalchuk, O;Pogribny, IP
癌细胞的特征是表观遗传失调，包括全球基因组低甲基化、局部低甲基化和高甲基化、组蛋白修饰改变和基因组印迹紊乱。尽管长期以来的事实是，全球DNA低甲基化是肿瘤的一个共同特征，但对这种低甲基化和其他表观遗传学变化在肿瘤进展过程中的进化知之甚少。本研究旨在研究代表乳腺癌不同阶段的三种人乳腺癌细胞系(MCF-7、MDA-MB-231和MDA-MB-231(S30))的表观遗传异常状态。我们的数据显示，与非致癌的MCF-10-2A乳腺上皮细胞相比，乳腺癌细胞的细胞表观遗传状态发生了显著的变化。有趣的是，与MCF-7细胞相比，更恶性的MDA-MB-231人乳腺癌细胞具有更显著的DNA甲基化缺失，伴随着维持DNA甲基转移酶DNMT1、甲基结合蛋白MeCP2和Mbd2的表达改变，组蛋白H4的赖氨酸20的三甲基化和组蛋白H4的高乙酰化。在MDA-MB-231细胞中，组蛋白H4赖氨酸20三甲基化水平的降低伴随着Suv4-20h2组蛋白甲基转移酶表达的降低。目前的研究结果表明，MDA-MB-231细胞比MCF-7细胞具有更广泛的表观遗传改变。这些结果表明，人类乳腺癌细胞的特征是显著的表观遗传学改变，这与癌细胞恶性特性的增加有关。这种表观遗传失调可能有助于并可能预示着在肿瘤进展过程中形成更具侵袭性的肿瘤表型。
Cancer cells are characterized by epigenetic dysregulation, including global genome hypomethylation, regional hypo- and hypermethylation, altered histone modifications, and disturbed genomic imprinting. Despite the long-established fact that global DNA hypomethylation is a common feature of tumors, very little is known about evolution of this and other epigenetic alterations during tumor progression. The present study was undertaken to characterize the status of epigenetic dysregulation in three human breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-231(S30) that represent different stages of human breast cancer. Our data show that breast cancer cells are characterized by significant alterations in cellular epigenetic status compared to non-tumorigenic MCF-10-2A epithelial breast cells. Interestingly, more malignant MDA-MB-231 human breast cancer cells have a more prominent loss of DNA methylation accompanied by altered expression of maintenance DNA methyltransferase DNMT1, methyl-binding proteins MeCP2 and MBD2, decreased trimethylation of lysine 20 of histone H4 and hyperacetylation of histone H4 compared to MCF-7 cells. The decrease in trimethylation of lysine 20 of histone H4 in MDA-MB-231 cells was accompanied by diminished expression of Suv4-20h2 histone methyltransferase. The results of present study demonstrate that MDA-MB-231 cells have more extensive epigenenic alterations than MCF-7. These results demonstrate that human breast cancer cells are characterized by prominent epigenetic alterations which are associated with increased malignant properties of cancer cells. Such epigenetic dysregulation may contribute to and may be indicative of the formation of a more aggressive tumor phenotype during tumor progression.