Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2) in human oral cancer cell line.
Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2) in human oral cancer cell line.
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DOI：
10.1371/journal.pone.0012554
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发表时间：
2010-09-03
期刊：
影响因子：
3.7
通讯作者：
Tsuji T
中科院分区：
文献类型：
--
作者：
Yamamoto D;Shima K;Matsuo K;Nishioka T;Chen CY;Hu GF;Sasaki A;Tsuji T
基因组DNA的CpG岛和组蛋白H3和H4尾部的赖氨酸残基的甲基化调节基因转录。鸟氨酸脱羧酶抗酶-1（OAZ）抑制人口腔癌细胞系中多胺的合成，导致脱羧S-腺苷甲硫氨酸（dcSAM）的积累，其作为甲基化反应的竞争性抑制剂。我们预计dcSAM的积累会损害甲基化反应，并导致基因组DNA和组蛋白尾部的低甲基化。在存在或不存在OAZ表达的情况下，分别通过甲基化异构体（迈阿密）方法和蛋白质印迹法测定基因组DNA的整体甲基化状态和组蛋白H3和H4尾部的赖氨酸残基。OAZ的异位表达介导基因组DNA的CpG岛的低甲基化和组蛋白H3赖氨酸9二甲基化（H3 K9 me 2）。DNA甲基转移酶3B（DNMT 3B）和组蛋白H3 K9 me特异性甲基转移酶G9 a的蛋白水平在OAZ转染子中下调。OAZ通过下调DNMT 3B和G9 a蛋白水平诱导全局基因组DNA和H3 K9 me 2的CpG岛低甲基化。基因组DNA的CpG岛和组蛋白H3 K9 me 2的低甲基化是诱导肿瘤抑制和DNA双链断裂修复相关基因的有效机制。
Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ) in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM), which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails. Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI) method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2). Protein level of DNA methyltransferase 3B (DNMT3B) and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant. OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down-regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair.
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