1. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism
- Author
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Jorge Joven, Sara Verdura, Salvador Fernández-Arroyo, Elisa Blanco-González, Javier A. Menendez, Maria Montes-Bayón, Jan Stursa, R Á-F García, Elisabet Cuyàs, Benoit Viollet, Lukas Werner, Jiri Neuzil, Program Against Cancer Therapeutic Resistance/Metabolism & Cancer Group [Catalonia, Spain] (ProCURE), Catalan Institute of Oncology-Girona (ICO-Girona), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Unitat de Recerca Biomedica [Reus, Spain], Hospital Universitari de Sant Joan [Reus, Spain]-Rovira i Virgili University [Reus, Spain] (IISPV), The Campus of International Excellence Southern Catalonia [Tarragona, Spain], Department of Physical and Analytical Chemistry oviedo [Oviedo, Spain] ( Faculty of Chemistry), University of Oviedo, Institute of Chemical Technology [Prague, Czech Republic], Institute of Biotechnology [Prague-West, Czech Republic], Czech Academy of Sciences [Prague] (CAS), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Medical Science [Queensland, Australia], Griffith University [Brisbane], and Viollet, Benoit
- Subjects
0301 basic medicine ,S-Adenosylmethionine ,Cancer Research ,Methyltransferase ,AMP-Activated Protein Kinases ,Mitochondrion ,MESH: Metformin ,Mice ,MESH: DNA Methylation ,Tumor Cells, Cultured ,MESH: Animals ,MESH: AMP-Activated Protein Kinases ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Regulation of gene expression ,MESH: Electron Transport Complex I ,Biguanide ,MESH: Follow-Up Studies ,MESH: Gene Expression Regulation, Neoplastic ,Methylation ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,S-Adenosylhomocysteine ,Metformin ,Mitochondria ,Cell biology ,Gene Expression Regulation, Neoplastic ,Colonic Neoplasms ,DNA methylation ,Female ,MESH: Biomarkers, Tumor ,Reprogramming ,medicine.drug ,MESH: S-Adenosylhomocysteine ,MESH: Mitochondria ,medicine.drug_class ,MESH: Carbon ,Breast Neoplasms ,Biology ,03 medical and health sciences ,MESH: Hypoglycemic Agents ,Biomarkers, Tumor ,Genetics ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,MESH: Tumor Cells, Cultured ,MESH: Mice ,Molecular Biology ,MESH: Genome, Human ,MESH: Colonic Neoplasms ,MESH: Humans ,Electron Transport Complex I ,Genome, Human ,MESH: S-Adenosylmethionine ,DNA Methylation ,Carbon ,030104 developmental biology ,MESH: Female ,MESH: Breast Neoplasms ,Follow-Up Studies - Abstract
International audience; 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.
- Published
- 2017
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