Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism
Artikel i vetenskaplig tidskrift, 2014

Background Succinate dehydrogenase (SDH) is a mitochondrial metabolic enzyme complex involved in both the electron transport chain and the citric acid cycle. SDH mutations resulting in enzymatic dysfunction have been found to be a predisposing factor in various hereditary cancers. Therefore, SDH has been implicated as a tumor suppressor. Results We identified that dysregulation of SDH components also occurs in serous ovarian cancer, particularly the SDH subunit SDHB. Targeted knockdown of Sdhb in mouse ovarian cancer cells resulted in enhanced proliferation and an epithelial-to-mesenchymal transition (EMT). Bioinformatics analysis revealed that decreased SDHB expression leads to a transcriptional upregulation of genes involved in metabolic networks affecting histone methylation. We confirmed that Sdhb knockdown leads to a hypermethylated epigenome that is sufficient to promote EMT. Metabolically, the loss of Sdhb resulted in reprogrammed carbon source utilization and mitochondrial dysfunction. This altered metabolic state of Sdhb knockdown cells rendered them hypersensitive to energy stress. Conclusions These data illustrate how SDH dysfunction alters the epigenetic and metabolic landscape in ovarian cancer. By analyzing the involvement of this enzyme in transcriptional and metabolic networks, we find a metabolic Achilles’ heel that can be exploited therapeutically. Analyses of this type provide an understanding how specific perturbations in cancer metabolism may lead to novel anticancer strategies.

Epigenetics

Carbon metabolism

Ovarian cancer

Succinate dehydrogenase

EMT

SDH

Författare

P-J. Aspuria

S.Y. Lunt

Leif Wigge

Chalmers, Kemi- och bioteknik, Livsvetenskaper, Systembiologi

L. Vergnes

M. Gozo

J.A. Beach

B. Salumbides

K. Reue

W.R. Wiedemeyer

Jens B Nielsen

Chalmers, Kemi- och bioteknik, Livsvetenskaper, Systembiologi

B.Y. Karlan

S. Orsulic

Cancer & Metabolism

2049-3002 (ISSN)

Vol. 2

Ämneskategorier

Biologiska vetenskaper

Infrastruktur

C3SE (Chalmers Centre for Computational Science and Engineering)

Styrkeområden

Livsvetenskaper och teknik

DOI

10.1186/2049-3002-2-21