Metformin alters DNA methylation genome-wide via the H19/SAHH axis.
Metformin alters DNA methylation genome-wide via the H19/SAHH axis.
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二甲双胍通过 H19/SAHH 轴改变全基因组 DNA 甲基化
DOI：
10.1038/onc.2016.391
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发表时间：
2017-04-27
期刊：
影响因子：
8
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Zhong T;Men Y;Lu L;Geng T;Zhou J;Mitsuhashi A;Shozu M;Maihle NJ;Carmichael GG;Taylor HS;Huang Y
二甲双胍是一种治疗2型糖尿病的一线药物，其抗肿瘤作用的分子机制仍然难以捉摸。在此，我们报道了二甲双胍通过调节S同型半胱氨酸腺苷水解酶的活性来诱导全基因组甲基化的改变。将癌细胞暴露在二甲双胍中会导致肿瘤促进途径基因的高甲基化，并伴随着细胞增殖的抑制。二甲双胍的作用是通过AMPK激活上调microRNA let-7，导致H19长非编码RNA的降解，H19非编码RNA通常与SAHH结合并失活。H19基因敲除可激活SAHH，使DNA甲基转移酶3B能够甲基化一组基因。从服用抗糖尿病剂量的二甲双胍治疗的患者获得的子宫内膜癌组织样本中，重复了这种二甲双胍诱导的H19抑制和基因甲基化改变。我们的发现揭示了药物二甲双胍的一种新的作用机制，并暗示了癌症表观遗传失调的分子基础。这种新的作用机制也可能发生在正常细胞中。
The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH. H19 knockdown activates SAHH, enabling DNA methyltransferase 3B to methylate a subset of genes. This metformin-induced H19 repression and alteration of gene methylation are recapitulated in endometrial cancer tissue samples obtained from patients treated with antidiabetic doses of metformin. Our findings unveil a novel mechanism of action for the drug metformin with implications for the molecular basis of epigenetic dysregulation in cancer. This novel mechanism of action also may be occurring in normal cells.