Metformin alters DNA methylation genome-wide via the H19/SAHH axis

T. Zhong, Y. Men, L. Lu, T. Geng, J. Zhou, A. Mitsuhashi, M. Shozu, Nita Jane Maihle, G. G. Carmichael, H. S. Taylor, Y. Huang

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2345-2354
Number of pages10
JournalOncogene
Volume36
Issue number17
DOIs
StatePublished - Apr 27 2017

Fingerprint

Adenosylhomocysteinase
Metformin
DNA Methylation
Genome
Genes
Neoplasms
AMP-Activated Protein Kinases
Endometrial Neoplasms
MicroRNAs
Hypoglycemic Agents
Epigenomics
Pharmaceutical Preparations
Antineoplastic Agents
Type 2 Diabetes Mellitus
Methylation
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zhong, T., Men, Y., Lu, L., Geng, T., Zhou, J., Mitsuhashi, A., ... Huang, Y. (2017). Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene, 36(17), 2345-2354. https://doi.org/10.1038/onc.2016.391

Metformin alters DNA methylation genome-wide via the H19/SAHH axis. / Zhong, T.; Men, Y.; Lu, L.; Geng, T.; Zhou, J.; Mitsuhashi, A.; Shozu, M.; Maihle, Nita Jane; Carmichael, G. G.; Taylor, H. S.; Huang, Y.

In: Oncogene, Vol. 36, No. 17, 27.04.2017, p. 2345-2354.

Research output: Contribution to journalArticle

Zhong, T, Men, Y, Lu, L, Geng, T, Zhou, J, Mitsuhashi, A, Shozu, M, Maihle, NJ, Carmichael, GG, Taylor, HS & Huang, Y 2017, 'Metformin alters DNA methylation genome-wide via the H19/SAHH axis', Oncogene, vol. 36, no. 17, pp. 2345-2354. https://doi.org/10.1038/onc.2016.391
Zhong T, Men Y, Lu L, Geng T, Zhou J, Mitsuhashi A et al. Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene. 2017 Apr 27;36(17):2345-2354. https://doi.org/10.1038/onc.2016.391
Zhong, T. ; Men, Y. ; Lu, L. ; Geng, T. ; Zhou, J. ; Mitsuhashi, A. ; Shozu, M. ; Maihle, Nita Jane ; Carmichael, G. G. ; Taylor, H. S. ; Huang, Y. / Metformin alters DNA methylation genome-wide via the H19/SAHH axis. In: Oncogene. 2017 ; Vol. 36, No. 17. pp. 2345-2354.
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