title: Metformin targets histone acetylation in cancer-prone epithelial cells.
abstract: The usage of metabolic intermediates as substrates for chromatin-modifying enzymes provides a direct link between the metabolic state of the cell and epigenetics. Because this metabolism-epigenetics axis can regulate not only normal but also diseased states, it is reasonable to suggest that manipulating the epigenome via metabolic interventions may improve the clinical manifestation of age-related diseases including cancer. Using a model of BRCA1 haploinsufficiency-driven accelerated geroncogenesis, we recently tested the hypothesis that: 1.) metabolic rewiring of the mitochondrial biosynthetic nodes that overproduce epigenetic metabolites such as acetyl-CoA should promote cancer-related acetylation of histone H3 marks; 2.) metformin-induced restriction of mitochondrial biosynthetic capacity should manifest in the epigenetic regulation of histone acetylation. We now provide one of the first examples of how metformin-driven metabolic shifts such as reduction of the 2-carbon epigenetic substrate acetyl-CoA is sufficient to correct specific histone H3 acetylation marks in cancer-prone human epithelial cells. The ability of metformin to regulate mitonuclear communication and modulate the epigenetic landscape in genomically unstable pre-cancerous cells might guide the development of new metabolo-epigenetic strategies for cancer prevention and therapy.
authors: a ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology , Girona , Catalonia , Spain.|b Girona Biomedical Research Institute (IDIBGI) , Girona , Catalonia , Spain.
authors: Elisabet
authors: E
authors: Cuyàs
authors: c Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain, The Campus of International Excellence Southern Catalonia , Tarragona , Spain.
authors: Salvador
authors: S
authors: Fernández-Arroyo
authors: c Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain, The Campus of International Excellence Southern Catalonia , Tarragona , Spain.
authors: Jorge
authors: J
authors: Joven
authors: a ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology , Girona , Catalonia , Spain.|b Girona Biomedical Research Institute (IDIBGI) , Girona , Catalonia , Spain.
authors: Javier A
authors: JA
authors: Menendez
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D019313:BRCA1 Protein / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D042822:Genomic Instability / Q000187:drug effects; D057895:Haploinsufficiency / Q000187:drug effects / Q000235:genetics; D006657:Histones; D008687:Metformin / Q000494:pharmacology*; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D006657:Histones; D000105:Acetyl Coenzyme A; D008687:Metformin
keywords: BRCA1; epigenetics; histone acetylation; metformin; mitochondria