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.
- MeSH
- genom lidský * MeSH
- hypoglykemika farmakologie MeSH
- lidé MeSH
- metformin farmakologie MeSH
- metylace DNA účinky léků MeSH
- mitochondrie účinky léků metabolismus patologie MeSH
- myši MeSH
- nádorové biomarkery MeSH
- nádorové buňky kultivované MeSH
- nádory prsu farmakoterapie enzymologie patologie MeSH
- nádory tračníku farmakoterapie enzymologie patologie MeSH
- následné studie MeSH
- proteinkinasy aktivované AMP metabolismus MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- respirační komplex I metabolismus MeSH
- S-adenosylhomocystein metabolismus MeSH
- S-adenosylmethionin metabolismus MeSH
- uhlík metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
