Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression
Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression
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DOI：
10.1073/pnas.94.20.10907
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Waalkes, MP
中科院分区：
文献类型：
--
作者：
Zhao, CQ;Young, MR;Waalkes, MP
无机砷是一种人类致癌物，它被酶促甲基化以解毒，在此过程中消耗S-腺苷甲硫氨酸（SAM），DNA甲基转移酶（MeTases）需要相同的甲基供体的事实表明甲基化在砷致癌中的作用。该假设通过以下方法进行了验证：首先通过长期暴露于低水平的砷在大鼠肝上皮细胞系中诱导转化，如通过将细胞接种到裸鼠中后高度侵袭性的恶性肿瘤的发展所证实的，整体DNA低甲基化与恶性转化同时发生，并且在S-腺苷甲硫氨酸水平降低的情况下，砷诱导的DNA低甲基化是剂量和暴露持续时间的函数，并且即使在撤回砷后仍保持恒定，在转化细胞中也检测到MT基因的过度表达，该基因的表达明显受DNA甲基化控制。急性砷或非转化水平的砷不诱导DNA的整体低甲基化，而DNA MeTase的转录升高，MeTase的酶活性随着砷转化而降低。总之，这些结果表明砷可以作为一种致癌物，通过诱导DNA低甲基化，这反过来又促进异常基因表达，他们构成了一个站得住脚的理论砷致癌机制。
Inorganic arsenic, a human carcinogen, is enzymatically methylated for detoxication, consuming s-adenosyl-methionine (SAM) in the process, The fact that DNA methyltransferases (MeTases) require this same methyl donor suggests a role for methylation in arsenic carcinogenesis Here we test the hypothesis that arsenic-induced initiation results from DNA hypomethylation caused by continuous methyl depletion, The hypothesis was tested by first inducing transformation in a rat liver epithelial cell line by chronic exposure to low levels of arsenic, as confirmed by the development of highly aggressive, malignant tumors after inoculation of cells into Nude mice, Global DNA hypomethylation occurred concurrently with malignant transformation and in the presence of depressed levels of S-adenosyl-methionine Arsenic-induced DNA hypomethylation was a function of dose and exposure duration, and remained constant even after withdrawal of arsenic, Hyperexpressibility of the MT gene, a gene for which expression is clearly controlled by DNA methylation, was also detected in transformed cells, Acute arsenic or arsenic at nontransforming levels did not induce global hypomethylation of DNA, Whereas transcription of DNA MeTase was elevated, the MeTase enzymatic activity was reduced with arsenic transformation. Taken together, these results indicate arsenic can act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression, and they constitute a tenable theory of mechanism in arsenic carcinogenesis.