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Oncogene. 2018 Feb 15;37(7):963-970. doi: 10.1038/onc.2017.367. Epub 2017 Oct 23.

Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism.

Author information

1
ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain.
2
Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain.
3
Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain.
4
The Campus of International Excellence Southern Catalonia, Tarragona, Spain.
5
Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, Oviedo, Spain.
6
Institute of Chemical Technology, Prague, Czech Republic.
7
Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic.
8
INSERM U1016, Institut Cochin, Paris, France.
9
CNRS UMR 8104, Paris, France.
10
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
11
School of Medical Science, Griffith University, Southport, Queensland, Australia.

Abstract

The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM:SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity. By increasing the contribution of one-carbon units to the SAM from folate stores while decreasing SAH in response to AMPK-sensed energetic crisis, metformin can operate as a metabolo-epigenetic regulator capable of reprogramming one of the key conduits linking cellular metabolism to the DNA methylation machinery.

PMID:
29059169
DOI:
10.1038/onc.2017.367

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