Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

Abstract

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.

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 ).…”

Biomarkers of Immunotherapy Response in Patients with Non-Small-Cell Lung Cancer: Microbiota Composition, Short-Chain Fatty Acids, and Intestinal Permeability

“…Of the SCFAs, butyrate is the most closely related to oncological processes and has been proposed as an inhibitor of cancer cell proliferation, with direct antineoplastic effects due to the interactions with histone deacetylase enzymes [ 38 , 39 ]. Propionate administration has therapeutic potential in reducing NSCLC aggressiveness and warrants further clinical testing [ 40 ]. Locally in the lungs, SCFAs might stimulate regulatory T cells, T helper 2 cells, and interleukin 22+ type 3 innate lymphoid cells to protect against airway inflammation via T-cell receptor signaling [ 41 ].…”