Metformin alters DNA methylation genome-wide via the H19/SAHH axis
Open accessAbstract
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.
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In cancer cells, metformin promotes global DNA methylation via the H19/SAHH axis.
“and in cancer cells via the H19/S-adenosylhomocysteine hydrolase (SAHH) axis (Cuyàs et al. 2017, Zhong et al. 2017).”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Zhong et al. 2017
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Benefits of Metformin in Attenuating the Hallmarks of Aging
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- Authors
- Zhong, T., Men, Y., Lu, L., Geng, T., Zhou, J., Mitsuhashi, A., Shozu, M., Maihle, N. J., Carmichael, G. G., Taylor, H. S., & Huang, Y.
- Affiliations
- Yale University (US)
- Sichuan University (CN)
- Sir Run Run Shaw Hospital (CN)
- Chiba University (JP)
- Augusta University (US)
- UConn Health (US)
- Corresponding author
- Huang, Y
- Venue
- Oncogene
- Published
- 2016-10-24
- Volume
- 36
- Issue
- 17
- Pages
- 2345-2354
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC5415944
- OpenAlex
- W2537254995
- Cited by
- 151
- References
- 32
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 12 · 2023: 13 · 2022: 20 · 2021: 29 · 2020: 20 · 2019: 14 · 2018: 17 · 2017: 7
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Oncogene (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81602471)
- National Institutes of Health (UL1TR001863)
- Japan Society for the Promotion of Science (15K10702)
- National Institute of General Medical Sciences
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD072418)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- metformin, DNA methylation, S-adenosylhomocysteine hydrolase, let-7 microRNA, AMPK signaling, DNMT3B, endometrial cancer, epigenetic dysregulation, type 2 diabetes
- MeSH terms
- DNA Methyltransferase 3B, DNA (Cytosine-5-)-Methyltransferases, Enzyme Activation, Humans, Metformin, Signal Transduction, Up-Regulation, DNA Methylation, RNA Stability, Genomics, MicroRNAs, Adenosylhomocysteinase, AMP-Activated Protein Kinases, MCF-7 Cells, RNA, Long Noncoding, Carcinogenesis
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