Propionate reinforces epithelial identity and reduces aggressiveness of non-small cell lung carcinoma via chromatin remodelling

Ramesh, V.; Gollavilli, P. N.; Pinna, L.; Siddiqui, M. A.; Jakobsen, S. T.; Boiteux, E. L.; Olsen, K. E.; Jensen, O. N.; Siersbaek, R.; Somyajit, K.; Ceppi, P.

doi:10.1101/2023.01.19.524677

bioRxiv · 10.1101/2023.01.19.524677

Propionate reinforces epithelial identity and reduces aggressiveness of non-small cell lung carcinoma via chromatin remodelling

Ramesh, V.·Gollavilli, P. N.·Pinna, L.·Siddiqui, M. A.·Jakobsen, S. T.·Boiteux, E. L.·Olsen, K. E.·Jensen, O. N.·Siersbaek, R.·Somyajit, K.·Ceppi, P.

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Abstract

Epithelial to mesenchymal transition (EMT) is a developmental cellular program driving metastasis and chemo-resistance in cancer, but its pharmacological treatment has been so far challenging. Targeting deregulated metabolic processes in cancer is emerging as a realistic therapeutic strategy. Here, we used an EMT-focussed integrative functional genomic approach and identified negative association of the short-chain fatty acids propionate and butanoate with EMT in non-small cell lung cancer (NSCLC) patients. Strikingly, in vitro treatment of lung cancer cell lines with propionate reinforced the epithelial transcriptional program promoting cell adhesion and reverting the aggressive and chemoresistant EMT phenotype. Propionate treatment reduced cells metastatic ability in nude mice and limited lymph nodal spread in a genetic NSCLC mouse model. Further analyses indicated chromatin remodeling via H3K27 acetylation (p300-mediated) as the mechanism shifting the EMT balance towards epithelial state upon propionate. Propionate administration could be tested in the clinic for reducing NSCLC aggressiveness. HighlightsAn EMT-centric investigation of metabolic processes in a comprehensive lung cancer transcriptome profiles identified negative associations between EMT and SCFAs (propionate and butyrate) Propionate enhances the epithelial features both at the molecular and cellular levels Pre-treatment of cells with propionate inhibits EMT associated processes including migration and sensitizes the cells to chemotherapeutic drug cisplatin Oral administration of propionate inhibits EMT-mediated lung colonization ability of NSCLC cells, and lymph node metastasis in a genetic mouse NSCLC model Molecular mechanistic investigation of propionate revealed chromatin remodelling through p300-mediated histone acetylation in E-cadherin gene regulation along with epithelial features reinforcement

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Ramesh, V., Gollavilli, P. N., Pinna, L., Siddiqui, M. A., Jakobsen, S. T., Boiteux, E. L., Olsen, K. E., Jensen, O. N., Siersbaek, R., Somyajit, K., Ceppi, P.. 2023-01-20. Propionate reinforces epithelial identity and reduces aggressiveness of non-small cell lung carcinoma via chromatin remodelling. https://doi.org/10.1101/2023.01.19.524677

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