Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

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.
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Submitted on : Tuesday, November 5, 2019 - 8:03:00 PM
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E Cuyàs, S Fernández-Arroyo, S Verdura, R Á-F García, J Stursa, et al.. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism. Oncogene, Nature Publishing Group, 2018, 37 (7), pp.963-970. ⟨10.1038/onc.2017.367⟩. ⟨inserm-02349919⟩

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