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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; Karlan, Beth Y.; Orsulic, Sandra (2014)
Publisher: BioMed Central Ltd.
Journal: Cancer & Metabolism
Languages: English
Types: Article
Subjects: Ovarian cancer, SDH, EMT, Carbon metabolism, Research, Epigenetics, Succinate dehydrogenase

Classified by OpenAIRE into

mesheuropmc: macromolecular substances
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. Electronic supplementary material The online version of this article (doi:10.1186/2049-3002-2-21) contains supplementary material, which is available to authorized users.

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