Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases
Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases
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DOI：
10.1158/0008-5472.can-04-2957
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发表时间：
2005-07-15
期刊：
影响因子：
11.2
通讯作者：
Lyko, F
中科院分区：
文献类型：
--
作者：
Brueckner, B;Boy, RG;Lyko, F
DNA甲基化调节正常和恶性细胞中的基因表达。重新激活表观遗传沉默的基因的可能性引起了人们对DNA甲基转移酶抑制剂开发的极大兴趣。在这里，我们提供了RG108的详细特征，RG108是一种新的小分子，在体外有效地阻断DNA甲基转移酶，并且不会在人类细胞系中引起共价酶捕获。用该化合物的低微摩尔浓度孵育细胞，可导致基因组DNA显著去甲基化，而没有检测到任何毒性。有趣的是，RG108导致肿瘤抑制基因去甲基化和重新激活，但它不影响着丝粒卫星序列的甲基化。这些结果证明RG108是一种具有基本新颖特性的DNA甲基转移酶抑制剂，这将对表观遗传基因调控的实验调节特别有用。
DNA methylation regulates gene expression in normal and malignant cells. The possibility to reactivate epigenetically silenced genes has generated considerable interest in the development of DNA methyltransferase inhibitors. Here, we provide a detailed characterization of RG108, a novel small molecule that effectively blocked DNA methyltransferases in vitro and did not cause covalent enzyme trapping in human cell lines. Incubation of cells with low micromolar concentrations of the compound resulted in significant demethylation of genomic DNA without any detectable toxicity. Intriguingly, RG108 caused demethylation and reactivation of tumor suppressor genes, but it did not affect the methylation of centromeric satellite sequences. These results establish RG108 as a DNA methyltransferase inhibitor with fundamentally novel characteristics that will be particularly useful for the experimental modulation of epigenetic gene regulation.