Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism
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2049-3002-2-21.pdf
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Author(s)
Aspuria, Paul-Joseph P.
Lunt, Sophia Yunkyungkwon
Väremo, Leif
Vergnes, Laurent
Gozo, Maricel
Beach, Jessica A
Salumbides, Brenda
Reue, Karen
Wiedemeyer, W. R.
Nielsen, Jens Kromann
Date Issued
December 2014
Journal
Cancer & Metabolism
Publisher
BioMed Central Ltd.
Citation
Aspuria, Paul-Joseph P., Sophia Y. Lunt, Leif Varemo, Laurent Vergnes et al. "Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism." Cancer & Metabolism. (2014 Dec 15); 2 (1):21.
Version
Final published version
Abstract
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.
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.
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
http://dx.doi.org/10.1186/2049-3002-2-21
