Article open access publication

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

Cancer & Metabolism, Springer Nature, ISSN 2049-3002

Volume 7, 1, 2019

DOI:10.1186/s40170-019-0197-8, Dimensions: pub.1116204198, PMC: PMC6544948, PMID: 31164982,

Affiliations

Organisations

  1. (1) University of Bergen, grid.7914.b
  2. (2) Ain Shams University, grid.7269.a
  3. (3) National University of Singapore, grid.4280.e
  4. (4) Haukeland University Hospital, grid.412008.f
  5. (5) University of Southern Denmark, grid.10825.3e, SDU
  6. (6) University of Iceland, grid.14013.37
  7. (7) Odense University Hospital, grid.7143.1, Southern Denmark Region
  8. (8) Institut Gustave Roussy, grid.14925.3b
  9. (9) Institute of Molecular and Cell Biology, grid.418812.6

Description

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.

Funders

Research Categories

Main Subject Area

Fields of Research

Links & Metrics

NORA University Profiles

University of Southern Denmark

Dimensions Citation Indicators

Times Cited: 14

Open Access Info

Pure Gold