The short-chain fatty acid acetate modulates epithelial-to-mesenchymal transition

Normal tissue and organ morphogenesis requires epithelial cell plasticity and conversion to a mesenchymal phenotype through a tightly regulated process-epithelial-to-mesenchymal transition (EMT). Alterations of EMT go far beyond cell-lineage segregation and contribute to pathologic conditions such as cancer. EMT is subject to intersecting control pathways; however, EMT's metabolic mechanism remains poorly understood. Here, we demonstrate that transforming growth factor beta (TGF-beta)-induced EMT is accompanied by decreased fatty acid oxidation (FAO) and reduced acetyl-coenzyme A (acetyl-CoA) levels. Acetyl-CoA is a central metabolite and the sole donor of acetyl groups to acetylate key proteins. Further, the short-chain fatty acid acetate increases acetyl-CoA levels--robustly inhibiting EMT and cancer cell migration. Acetate can restore EMT-associated a-tubulin acetylation levels, increasing microtubule stability. Transcriptome profiling and flow cytometric analysis show that acetate inhibits the global gene expression program associated with EMT and the EMT-associated G1 cell cycle arrest. Taken together, these results demonstrate that acetate is a potent metabolic regulator of EMT and that therapeutic manipulation of acetate metabolism could provide the basis for treating a wide range of EMT-linked pathological conditions, including cancer.

Automated summary

Normal tissue and organ morphogenesis require epithelial cell plasticity and conversion to a mesenchymal phenotype through a process known as epithelial-to-mesenchymal transition (EMT). This study demonstrates that EMT induced by transforming growth factor beta (TGF-beta) is accompanied by reduced fatty acid oxidation (FAO) and decreased levels of acetyl-coenzyme A (acetyl-CoA). Acetate, a short-chain fatty acid, effectively inhibits EMT and cancer cell migration by increasing acetyl-CoA levels and restoring α-tubulin acetylation. These findings suggest that acetate is a potent metabolic regulator of EMT and targeting acetate metabolism could have therapeutic potential for EMT-related pathological conditions.