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

• Published in: Molecular biology of the cell Vol. 33; no. 8; p. mbcE22020066
• Main Authors: Lyu, Junfang, Pirooznia, Mehdi, Li, Yuesheng, Xiong, Jianhua
• Format: Journal Article
• Language: English
• Published: United States American Society for Cell Biology 01.07.2022; The American Society for Cell Biology
• Subjects: Acetates; Analysis; Brief Reports; Enzymes; Epithelial cells; Fatty acids; Gene expression; Genes; Health aspects; Identification and classification; Metabolites; Metastasis; Properties; Stem cells; Transforming growth factors; Tubulins; United States; California
• ISSN: 1059-1524; 1939-4586; 1939-4586
• DOI: 10.1091/mbc.E22-02-0066

Epithelial-to-mesenchymal transition (EMT) has been linked to various human diseases including cancer. The underlying metabolic regulators, however, remain poorly understood. Here we show how the short-chain fatty acid acetate restrains EMT. Our findings indicate that acetate is a potent metabolic regulator of EMT. 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 β (TGF-β)–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 α-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.