Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

Author:

Ramesh Vignesh12,Gollavilli Paradesi Naidu12,Pinna Luisa1,Siddiqui Mohammad Aarif1,Turtos Adriana Martinez1ORCID,Napoli Francesca3,Antonelli Yasmin4,Leal‐Egaña Aldo4ORCID,Havelund Jesper Foged1ORCID,Jakobsen Simon Toftholm1ORCID,Boiteux Elisa Le1,Volante Marco3,Færgeman Nils Joakim1ORCID,Jensen Ole N1ORCID,Siersbæk Rasmus1ORCID,Somyajit Kumar1,Ceppi Paolo12ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology University of Southern Denmark Odense Denmark

2. Interdisciplinary Centre for Clinical Research University Hospital Erlangen, FAU‐Erlangen‐Nuremberg Erlangen Germany

3. Department of Oncology at San Luigi Hospital University of Turin Turin Italy

4. Institute for Molecular Systems Engineering and Advanced Materials Heidelberg University Heidelberg Germany

Abstract

AbstractThe 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.

Funder

Kræftens Bekæmpelse

Dementia Collaborative Research Centres, Australia

Lundbeckfonden

Novo Nordisk Fonden

Villum Fonden

Publisher

Springer Science and Business Media LLC

Subject

Molecular Medicine

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