Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism
Journal article, 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.
Ovarian cancer
Succinate dehydrogenase
EMT
Epigenetics
Carbon metabolism
SDH
Author
P-J. Aspuria
Cedars-Sinai Medical Center
S.Y. Lunt
Massachusetts Institute of Technology (MIT)
Michigan State University
Leif Wigge
Chalmers, Chemical and Biological Engineering, Life Sciences
L. Vergnes
University of California
M. Gozo
Cedars-Sinai Medical Center
J.A. Beach
Cedars-Sinai Medical Center
B. Salumbides
Cedars-Sinai Medical Center
K. Reue
University of California
W.R. Wiedemeyer
University of California at Los Angeles
Cedars-Sinai Medical Center
Jens B Nielsen
Chalmers, Chemical and Biological Engineering, Life Sciences
B.Y. Karlan
Cedars-Sinai Medical Center
University of California at Los Angeles
S. Orsulic
Cedars-Sinai Medical Center
University of California at Los Angeles
Cancer & Metabolism
2049-3002 (ISSN)
Vol. 2Subject Categories
Biological Sciences
Infrastructure
C3SE (Chalmers Centre for Computational Science and Engineering)
Areas of Advance
Life Science Engineering (2010-2018)
DOI
10.1186/2049-3002-2-21
PubMed
25671108