The Warburg Effect Causes a Shift in Histone Acetylation

Links between cellular metabolism and gene expression are beginning to be appreciated, but these connections are complex and our mechanistic understanding remains limited. Butyrate is a fatty-acid byproduct of fiber fermentation by bacteria in the colon that is the main energy source of normal colonocytes but also has histone deacetylase (HDAC) inhibitor activity and can inhibit the growth of cancer cells. Donohoe and colleagues therefore hypothesized that this paradox might be due to inherent metabolic differences between normal and malignant cells. Unlike normal cells, which primarily generate energy through oxidative phosphorylation, cancer cells rely on aerobic glycolysis, a phenomenon known as the Warburg effect. When the Warburg effect was prevented in cancer cells, low doses of butyrate stimulated cell growth instead of causing cell death. The authors found that in normal cells, butyrate was metabolized as an oxidative energy source to stimulate cell growth, but in the presence of the Warburg effect or at higher butyrate doses that exceeded cellular metabolic capacity butyrate accumulated in the nucleus and increased global acetylation levels and cell death in a dose-dependent manner. Interestingly, in normal cells, metabolism of butyrate to acetyl-coA also stimulated histone acetyltransferase activity, suggesting that butyrate can stimulate histone acetylation through multiple mechanisms. However, gene expression profiling and chromatin immunoprecipitation showed that different genes were affected by these different butyrate-dependent mechanisms, with genes affected by metabolized butyrate enriched for those associated with cell proliferation, and targets of the HDAC inhibitor activity of butyrate enriched for genes associated with cell death. These findings thus establish a mechanistic link between cellular energy metabolism and gene regulation and provide insight into how gradients of butyrate produced by the intestinal microbiota might affect colonic homeostasis.

Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 2012 Oct 11 [Epub ahead of print].