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Epithelial to mesenchymal transition (EMT) is associated with attenuation of succinate dehydrogenase (SDH) in breast cancer through reduced expression of SDHC

Authors :
Gro V. Røsland
Sissel E. Dyrstad
Deusdedit Tusubira
Reham Helwa
Tuan Zea Tan
Maria L. Lotsberg
Ina K. N. Pettersen
Anna Berg
Charlotte Kindt
Fredrik Hoel
Kirstine Jacobsen
Ari J. Arason
Agnete S. T. Engelsen
Henrik J. Ditzel
Per E. Lønning
Camilla Krakstad
Jean P. Thiery
James B. Lorens
Stian Knappskog
Karl J. Tronstad
Source :
Cancer & Metabolism, Vol 7, Iss 1, Pp 1-18 (2019)
Publication Year :
2019
Publisher :
BMC, 2019.

Abstract

Abstract Background Epithelial to mesenchymal transition (EMT) is a well-characterized process of cell plasticity that may involve metabolic rewiring. In cancer, EMT is associated with malignant progression, tumor heterogeneity, and therapy resistance. In this study, we investigated the role of succinate dehydrogenase (SDH) as a potential key regulator of EMT. Methods Associations between SDH subunits and EMT were explored in gene expression data from breast cancer patient cohorts, followed by in-depth studies of SDH suppression as a potential mediator of EMT in cultured cells. Results We found an overall inverse association between EMT and the SDH subunit C (SDHC) when analyzing gene expression in breast tumors. This was particularly evident in carcinomas of basal-like molecular subtype compared to non-basal-like tumors, and a low SDHC expression level tended to have a prognostic impact in those patients. Studies in cultured cells revealed that EMT was induced by SDH inhibition through SDHC CRISPR/Cas9 knockdown or by the enzymatic inhibitor malonate. Conversely, overexpression of EMT-promoting transcription factors TWIST and SNAI2 caused decreased levels of SDHB and C and reduced rates of SDH-linked mitochondrial respiration. Cells overexpressing TWIST had reduced mitochondrial mass, and the organelles were thinner and more fragmented compared to controls. Conclusions Our findings suggest that downregulation of SDHC promotes EMT and that this is accompanied by structural remodeling of the mitochondrial organelles. This may confer survival benefits upon exposure to hostile microenvironment including oxidative stress and hypoxia during cancer progression.

Details

Language :
English
ISSN :
20493002
Volume :
7
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cancer & Metabolism
Publication Type :
Academic Journal
Accession number :
edsdoj.34446e854aaf4dda922810b5f57564ec
Document Type :
article
Full Text :
https://doi.org/10.1186/s40170-019-0197-8