Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

Vignesh Ramesh; Paradesi Naidu Gollavilli; Luisa Pinna; Mohammad Aarif Siddiqui; Adriana Martinez Turtos; Francesca Napoli; Yasmin Antonelli; Aldo Leal-Egaña; Jesper Foged Havelund; Simon Toftholm Jakobsen; Elisa Le Boiteux; Marco Volante; Nils Joakim Faergeman; Ole N Jensen; Rasmus Siersbaek; Kumar Somyajit; Paolo Ceppi

doi:10.15252/emmm.202317836

Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

Vignesh Ramesh, Paradesi Naidu Gollavilli, Luisa Pinna, Mohammad Aarif Siddiqui, Adriana Martinez Turtos, Francesca Napoli, Yasmin Antonelli, Aldo Leal-Egaña, Jesper Foged Havelund, Simon Toftholm Jakobsen, Elisa Le Boiteux, Marco Volante, Nils Joakim Faergeman, Ole N Jensen, Rasmus Siersbaek, Kumar Somyajit, Paolo Ceppi

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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.

Original language	English
Article number	e17836
Journal	EMBO Molecular Medicine
Volume	15
Issue number	12
ISSN	1757-4676
DOIs	https://doi.org/10.15252/emmm.202317836
Publication status	Published - 7. Dec 2023

Keywords

H3K27 acetylation
epithelial–mesenchymal transition
metabolic inhibitor
metastasis
propionate
Lung/metabolism
Humans
Gene Expression Regulation, Neoplastic
Propionates/pharmacology
Lung Neoplasms/genetics
Animals
Carcinoma, Non-Small-Cell Lung/genetics
Mice, Nude
Epithelial-Mesenchymal Transition
Cell Line, Tumor
Mice
Cell Movement

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10.15252/emmm.202317836Licence: CC BY

Open Access VersionFinal published version, 10.7 MBLicence: CC BY

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Ramesh, V., Gollavilli, P. N., Pinna, L., Siddiqui, M. A., Turtos, A. M., Napoli, F., Antonelli, Y., Leal-Egaña, A., Havelund, J. F., Jakobsen, S. T., Boiteux, E. L., Volante, M., Faergeman, N. J., Jensen, O. N., Siersbaek, R., Somyajit, K., & Ceppi, P. (2023). Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma. EMBO Molecular Medicine, 15(12), Article e17836. https://doi.org/10.15252/emmm.202317836

@article{659639d930bb4f5aa08b4b3eb588811b,

title = "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.",

keywords = "H3K27 acetylation, epithelial–mesenchymal transition, metabolic inhibitor, metastasis, propionate, Lung/metabolism, Humans, Gene Expression Regulation, Neoplastic, Propionates/pharmacology, Lung Neoplasms/genetics, Animals, Carcinoma, Non-Small-Cell Lung/genetics, Mice, Nude, Epithelial-Mesenchymal Transition, Cell Line, Tumor, Mice, Cell Movement",

author = "Vignesh Ramesh and Gollavilli, {Paradesi Naidu} and Luisa Pinna and Siddiqui, {Mohammad Aarif} and Turtos, {Adriana Martinez} and Francesca Napoli and Yasmin Antonelli and Aldo Leal-Ega{\~n}a and Havelund, {Jesper Foged} and Jakobsen, {Simon Toftholm} and Boiteux, {Elisa Le} and Marco Volante and Faergeman, {Nils Joakim} and Jensen, {Ole N} and Rasmus Siersbaek and Kumar Somyajit and Paolo Ceppi",

year = "2023",

month = dec,

day = "7",

doi = "10.15252/emmm.202317836",

language = "English",

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journal = "EMBO Molecular Medicine",

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Ramesh, V , Gollavilli, PN, Pinna, L, Siddiqui, MA , Turtos, AM, Napoli, F, Antonelli, Y, Leal-Egaña, A, Havelund, JF , Jakobsen, ST , Boiteux, EL, Volante, M, Faergeman, NJ , Jensen, ON , Siersbaek, R , Somyajit, K & Ceppi, P 2023, 'Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma', EMBO Molecular Medicine, vol. 15, no. 12, e17836. https://doi.org/10.15252/emmm.202317836

TY - JOUR

T1 - Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

AU - Ramesh, Vignesh

AU - Gollavilli, Paradesi Naidu

AU - Pinna, Luisa

AU - Siddiqui, Mohammad Aarif

AU - Turtos, Adriana Martinez

AU - Napoli, Francesca

AU - Antonelli, Yasmin

AU - Leal-Egaña, Aldo

AU - Havelund, Jesper Foged

AU - Jakobsen, Simon Toftholm

AU - Boiteux, Elisa Le

AU - Volante, Marco

AU - Faergeman, Nils Joakim

AU - Jensen, Ole N

AU - Siersbaek, Rasmus

AU - Somyajit, Kumar

AU - Ceppi, Paolo

PY - 2023/12/7

Y1 - 2023/12/7

N2 - 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.

AB - 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.

KW - H3K27 acetylation

KW - epithelial–mesenchymal transition

KW - metabolic inhibitor

KW - metastasis

KW - propionate

KW - Lung/metabolism

KW - Humans

KW - Gene Expression Regulation, Neoplastic

KW - Propionates/pharmacology

KW - Lung Neoplasms/genetics

KW - Animals

KW - Carcinoma, Non-Small-Cell Lung/genetics

KW - Mice, Nude

KW - Epithelial-Mesenchymal Transition

KW - Cell Line, Tumor

KW - Mice

KW - Cell Movement

U2 - 10.15252/emmm.202317836

DO - 10.15252/emmm.202317836

M3 - Journal article

C2 - 37766669

SN - 1757-4676

VL - 15

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 12

M1 - e17836

ER -

Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma

Abstract

Keywords

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