title: Metformin alters DNA methylation genome-wide via the H19/SAHH axis.
abstract: 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.
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.|Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
authors: T
authors: T
authors: Zhong
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.|Department of Head and Neck Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
authors: Y
authors: Y
authors: Men
authors: Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, CT, USA.
authors: L
authors: L
authors: Lu
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.|Department of Endocrinology, School of Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
authors: T
authors: T
authors: Geng
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.|Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors: J
authors: J
authors: Zhou
authors: Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: A
authors: A
authors: Mitsuhashi
authors: Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: M
authors: M
authors: Shozu
authors: Georgia Cancer Center, Medical College of Georgia, Augusta, GA, USA.
authors: N J
authors: NJ
authors: Maihle
authors: Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA.
authors: G G
authors: GG
authors: Carmichael
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
authors: H S
authors: HS
authors: Taylor
authors: Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.
authors: Y
authors: Y
authors: Huang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D043383:Adenosylhomocysteinase / Q000378:metabolism*; D063646:Carcinogenesis / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D023281:Genomics; D006801:Humans; D061986:MCF-7 Cells; D008687:Metformin / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000097584:DNA Methyltransferase 3B
chemical_list: D055372:AMP-Activated Protein Kinases; D043383:Adenosylhomocysteinase; D004248:DNA (Cytosine-5-)-Methyltransferases; D008687:Metformin; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D000097584:DNA Methyltransferase 3B; C094335:H19 long non-coding RNA; C487931:mirnlet7 microRNA, human