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

Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low-density lipoprotein receptor-deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft-bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

• MeSH
• biokatalýza MeSH
• experimentální nádory farmakoterapie   metabolismus   MeSH
• histondemethylasy antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• jaderné proteiny antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• metformin chemie   farmakologie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši knockoutované MeSH
• myši MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• beta-adrenergní receptory MeSH
• fosfatidylcholiny analýza   MeSH
• glukokortikoidy farmakologie   MeSH
• nemoci plodu diagnóza   MeSH
• plodová voda MeSH
• sfingomyeliny analýza   MeSH
• třetí trimestr těhotenství MeSH