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.