Metformin targets histone acetylation in cancer-prone epithelial cells.
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.
['Cuyàs|Elisabet|E|', 'Fernández-Arroyo|Salvador|S|', 'Joven|Jorge|J|', 'Menendez|Javier A|JA|']
D000105:Acetyl Coenzyme A D000107:Acetylation D019313:BRCA1 Protein D063646:Carcinogenesis D044127:Epigenesis, Genetic D004847:Epithelial Cells D042822:Genomic Instability D057895:Haploinsufficiency D006657:Histones D008687:Metformin D008954:Models, Biological D009369:Neoplasms
metformin histone acetylation epigenetics BRCA1 mitochondria