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

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.

Pan-cancer analysis of pyrimidine metabolism reveals signaling pathways connections with chemoresistance role

“…Furthermore, to examine the associations pattern at a single cell expression level, a single cell RNA sequencing of parental A549 cell line (untreated) was explored from our previous study (Ramesh et al , 2023), and the analysis revealed a consistent results of positive and negative association of the pathways with the pyrimidine metabolism across 5,203 cells ( Figure 2G ). Remarkably, a cluster-based analysis showed that pyrimidine and its associated positive signaling pathways or metabolic processes were strongly expressed in cluster 1 ( Figure 2H and Supplementary Figure S2D ).…”