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Succinate dehydroge...
Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism
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- Aspuria, P-J. (författare)
- Cedars-Sinai Medical Center
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- Lunt, S.Y. (författare)
- Massachusetts Institute of Technology (MIT),Michigan State University
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- Wigge, Leif, 1986 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology
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visa fler...
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- Vergnes, L. (författare)
- University of California
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- Gozo, M. (författare)
- Cedars-Sinai Medical Center
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- Beach, J.A. (författare)
- Cedars-Sinai Medical Center
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- Salumbides, B. (författare)
- Cedars-Sinai Medical Center
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- Reue, K. (författare)
- University of California
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- Wiedemeyer, W.R. (författare)
- University of California at Los Angeles (UCLA),Cedars-Sinai Medical Center
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- Nielsen, Jens B, 1962 (författare)
- Chalmers tekniska högskola,Chalmers University of Technology
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- Karlan, B.Y. (författare)
- Cedars-Sinai Medical Center,University of California at Los Angeles (UCLA)
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- Orsulic, S. (författare)
- Cedars-Sinai Medical Center,University of California at Los Angeles (UCLA)
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(creator_code:org_t)
- 2014-12-15
- 2014
- Engelska.
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Ingår i: Cancer & Metabolism. - : Springer Science and Business Media LLC. - 2049-3002. ; 2
- Relaterad länk:
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http://publications.... (primary) (free)
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https://cancerandmet...
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https://research.cha...
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https://research.cha...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- BackgroundSuccinate 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.ResultsWe 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.ConclusionsThese 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.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- Ovarian cancer
- Succinate dehydrogenase
- EMT
- Epigenetics
- Carbon metabolism
- SDH
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Aspuria, P-J.
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Lunt, S.Y.
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Wigge, Leif, 198 ...
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Vergnes, L.
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Gozo, M.
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Beach, J.A.
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visa fler...
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Salumbides, B.
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Reue, K.
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Wiedemeyer, W.R.
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Nielsen, Jens B, ...
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Karlan, B.Y.
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Orsulic, S.
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visa färre...
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- NATURVETENSKAP
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NATURVETENSKAP
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och Biologi
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Cancer & Metabol ...
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Chalmers tekniska högskola