Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

The epithelial-to-mesenchymal transition (EMT) plays a central role in the development of cancer metastasis and resistance to chemotherapy. However, its pharmacological treatment remains challenging. Here, we used an EMT-focused integrative functional genomic approach and identified an inverse association between short-chain fatty acids (propionate and butanoate) and EMT in non-small cell lung cancer (NSCLC) patients. Remarkably, treatment with propionate in vitro reinforced the epithelial transcriptional program promoting cell-to-cell contact and cell adhesion, while reducing the aggressive and chemo-resistant EMT phenotype in lung cancer cell lines. Propionate treatment also decreased the metastatic potential and limited lymph node spread in both nude mice and a genetic NSCLC mouse model. Further analysis revealed that chromatin remodeling through H3K27 acetylation (mediated by p300) is the mechanism underlying the shift toward an epithelial state upon propionate treatment. The results suggest that propionate administration has therapeutic potential in reducing NSCLC aggressiveness and warrants further clinical testing. imageAn EMT-centric investigation of metabolic processes in a comprehensive lung cancer transcriptome profiles collection identified an inverse association between EMT and SCFAs propionate and butyrate.Propionate enhances the epithelial features in vitro both at the molecular and cellular levelsPre-treatment of cells with propionate inhibits EMT-associated processes and sensitizes the cells to the chemotherapeutic drug cisplatinOral administration of propionate inhibits EMT-mediated lung colonization ability of NSCLC cells, and lymph node metastasis in a genetic mouse NSCLC modelMolecular mechanistic investigation revealed chromatin remodeling through p300-mediated histone acetylation in E-cadherin gene regulation along with epithelial features reinforcement An EMT-centric investigation of metabolic processes in a comprehensive lung cancer transcriptome profiles collection identified an inverse association between EMT and SCFAs propionate and butyrate.image