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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This work was supported in part by grants from the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P), Plan Nacional de I+D+I, Spain and the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (Grant 2014 SGR229), Department d’Economia I Coneixement, Catalonia, Spain, to Javier A Menendez and grants from the Czech Science Foundation (16-12816S) to Jan Stursa and Lukas Werner and the Czech Health Research Council (16-31704A) to Jiri Neuzil. Elisabet Cuyàs is supported by a Sara Borrell post-doctoral contract CD15/00033 from the Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), Spain, The Metabolism and Cancer laboratory is supported by an unrestricted grant from the Armangué family (Girona, Catalonia). This work is in memory of Joan Armangué who passed away after his brave fight against cancer in November 2016.
JAM conceived the idea, directed the project and wrote the manuscript. EC, SF-A, SV, RA-FG, MM-B and EB-G conducted metabolomic, ELISA-/HPLC-based DNA methylation and western blot experiments, and analyzed the data. JS and LW provided essential reagents. JN and BV provided essential reagents, intellectual insights and critical reading of the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Cuyàs, E., Fernández-Arroyo, S., Verdura, S. et al. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism. Oncogene 37, 963–970 (2018). https://doi.org/10.1038/onc.2017.367
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