Metformin targets histone acetylation in cancer-prone epithelial cells |
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Authors: | Elisabet Cuyàs Salvador Fernández-Arroyo Jorge Joven |
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Affiliation: | 1. ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism &2. Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain;3. Girona Biomedical Research Institute (IDIBGI), Girona, Catalonia, Spain;4. 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 |
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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. |
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Keywords: | BRCA1 epigenetics histone acetylation metformin mitochondria |
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