Mol. Cell, published online 9 October 2012; doi:10.1016/j.molcel.2012.08.033

Butyrate is a short-chain fatty acid and histone deacetylase (HDAC) inhibitor that has opposing effects on growth of normal and cancerous cells in the colon. Donohoe et al. now investigate the mechanisms underlying this paradox. The authors show that inhibition of the Warburg effect—aerobic glycolysis—blocks the inhibitory effects of low concentrations of butyrate on cell proliferation. On the basis of these findings, the authors hypothesized that butyrate is an oxidative energy source for normal cells, whereas it blocks proliferation of cancer cells because it inhibits HDACs. Inhibition of β-oxidation blocked butyrate's effects on proliferation of normal cells but not cancer cells. Inhibition of HDAC activity with trichostatin A (TSA) mimicked the activity of butyrate in cancer cells but had no effect on normal cells. Butyrate increased global histone acetylation in the context of the aerobic glycolysis but was more potent than would be predicted on the basis of its known half-maximum inhibitory concentration for target HDACs, so it might affect acetylation by additional mechanisms. Indeed, the authors showed that butyrate can increase acetylation in the presence of TSA, and metabolic flux experiments indicate butyrate can be a source for acetyl-CoA in cells and thereby stimulate histone acetyltransferase (HAT) activity. These data provide a mechanistic explanation for the butyrate paradox and demonstrate that butyrate can promote histone methylation by two mechanisms.