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Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

Cuyàs, E
Author Cuyàs, E ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
Fernández-Arroyo, S
Author Fernández-Arroyo, S Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain The Campus of International Excellence Southern Catalonia, Tarragona, Spain
Verdura, S
Author Verdura, S ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain
García, R Á-F
Author García, R Á-F Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, Oviedo, Spain
Stursa, J
Author Stursa, J Institute of Chemical Technology, Prague, Czech Republic Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic
Werner, L
Author Werner, L Institute of Chemical Technology, Prague, Czech Republic Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic
Blanco-González, E
Author Blanco-González, E Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, Oviedo, Spain
Montes-Bayón, M
Author Montes-Bayón, M Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, Oviedo, Spain
Joven, J
Author Joven, J Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain The Campus of International Excellence Southern Catalonia, Tarragona, Spain
Viollet, B
Author Viollet, B INSERM U1016, Institut Cochin, Paris, France CNRS UMR 8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Neuzil, J
Author Neuzil, J Institute of Chemical Technology, Prague, Czech Republic School of Medical Science, Griffith University, Southport, Queensland, Australia
Menendez, J A
Author Menendez, J A ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain

Oncogene. 2018 Feb 15 ; 37 (7) : 963-970. [epub] 20171023

ISSN 1476-5594 | 0950-9232
Source

Language English Country Great Britain, England Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid29059169

PubMed 29059169
DOI 10.1038/onc.2017.367
PII: onc2017367
Knihovny.cz E-resources

MeSH
Genome, Human * MeSH
Hypoglycemic Agents pharmacology MeSH
Humans MeSH
Metformin pharmacology MeSH
DNA Methylation drug effects MeSH
Mitochondria drug effects metabolism pathology MeSH
Mice MeSH
Biomarkers, Tumor MeSH
Tumor Cells, Cultured MeSH
Breast Neoplasms drug therapy enzymology pathology MeSH
Colonic Neoplasms drug therapy enzymology pathology MeSH
Follow-Up Studies MeSH
AMP-Activated Protein Kinases metabolism MeSH
Gene Expression Regulation, Neoplastic drug effects MeSH
Electron Transport Complex I metabolism MeSH
S-Adenosylhomocysteine metabolism MeSH
S-Adenosylmethionine metabolism MeSH
Carbon metabolism MeSH
Animals MeSH
Check Tag
Humans MeSH
Mice MeSH
Female MeSH
Animals MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
Hypoglycemic Agents MeSH
Metformin MeSH
Biomarkers, Tumor MeSH
AMP-Activated Protein Kinases MeSH
Electron Transport Complex I MeSH
S-Adenosylhomocysteine MeSH
S-Adenosylmethionine MeSH
Carbon MeSH

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.

CNRS UMR 8104 Paris France

Department of Physical and Analytical Chemistry Faculty of Chemistry University of Oviedo Oviedo Spain

Girona Biomedical Research Institute Girona Catalonia Spain

INSERM U1016 Institut Cochin Paris France

Institute of Biotechnology Czech Academy of Sciences Prague West Czech Republic

Institute of Chemical Technology Prague Czech Republic

ProCURE Metabolism and Cancer Group Catalan Institute of Oncology Girona Catalonia Spain

School of Medical Science Griffith University Southport Queensland Australia

The Campus of International Excellence Southern Catalonia Tarragona Spain

Unitat de Recerca Biomèdica Hospital Universitari Sant Joan Institut d'Investigació Sanitària Pere Virgili Universitat Rovira i Virgili Reus Spain

Université Paris Descartes Sorbonne Paris Cité Paris France

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