Butyrate induces apoptosis by activating PDC and inhibiting complex I through SIRT3 inactivation

The underlying anticancer effects of butyrate,an end-product of the intestinal microbial fermentation of dietary fiber,remain elusive.Here,we report that butyrate promotes cancer cell apoptosis by acting as a SIRT3 inhibitor.Butyrate inhibits SIRT3 both in cultured cells and in vitro.Butyrate-induced PDHA1 hyperacetylation relieves the inhibitory phosphorylation of PDHA1 at serine 293,thereby activating an influx of glycolytic intermediates into the tricarboxylic acid(TCA)cycle and reversing the Warburg effect.Meanwhile,butyrate-induced hyperacetylation inactivates complex I of the electron transfer chain and prevents the utilization of TCA cycle intermediates.These metabolic stresses promote apoptosis in hyperglycolytic cancer cells,such as HCT116p53^(−/−)cells.SIRT3 deacetylates both PDHA1 and complex I.Genetic ablation of Sirt3 in mouse hepatocytes abrogated the ability of butyrate to induce apoptosis.Our results identify a butyrate-mediated anti-tumor mechanism and indicate that the combined activation of PDC and inhibition of complex I is a novel tumor treatment strategy.