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Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism

P-J. Aspuria ; S.Y. Lunt ; Leif Väremo (Institutionen för kemi- och bioteknik, Systembiologi) ; L. Vergnes ; M. Gozo ; J.A. Beach ; B. Salumbides ; K. Reue ; W.R. Wiedemeyer ; Jens B. Nielsen (Institutionen för kemi- och bioteknik, Systembiologi) ; B.Y. Karlan ; S. Orsulic
Cancer & Metabolism (2049-3002). Vol. 2 (2014),
[Artikel, refereegranskad vetenskaplig]

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.

Nyckelord: Succinate dehydrogenase, SDH, Ovarian cancer, EMT, Carbon metabolism, Epigenetics

Denna post skapades 2015-01-19. Senast ändrad 2015-11-26.
CPL Pubid: 211058


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Institutioner (Chalmers)

Institutionen för kemi- och bioteknik, Systembiologi (2008-2014)


Biologiska vetenskaper

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C3SE/SNIC (Chalmers Centre for Computational Science and Engineering)