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

Abstract

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

There and back again: The journey of the estrogen-related receptors in the cancer realm

“…Migrating cells that have undergone EMT exhibit alterations in expression of metabolic enzymes and display metabolic profiles that are drastically different than those in proliferating cells [107]. Moreover, ablation of FASN and depletion of succinate dehydrogenase induces EMT in lung and ovarian cancer cells, respectively [107,108], implying that specific metabolic changes play crucial roles in mediating EMT. Lastly, the expression of GLUT3 is induced during EMT to support increased glucose consumption in mesenchymal cells [109].…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…These metabo lites are able to in hibit α ke tog lu tarate de pen dent dioxy ge nases among which the afore men tioned HIF 1α neg a tive reg u la tor PHD2 [214][215][216], but also TET fam ily of 5 methyl cy to sine hy drox y lases and Ju monji fam ily of hi s tone demethy lases [217][218][219], as pre vi ously dis cussed in para graph 2. In hi bi tion of the last two re sults in DNA and hi s tone hy per me thy la tion which, in turn, re presses miR 200 ex pres sion [220,221] and/ or in duces EMT re lated tran scrip tion fac tors [220], lead ing to re pres sion of ep ithe lial mark ers, ex pres sion of mes enchy mal mark ers, and ac qui si tion of mi gra tory and in va sive traits [213,220,222,223].…”

Increased efficacy of metformin corresponds to differential metabolic effects in ovarian tumors in obese versus lean mice

“…Lysolipids were also significantly increased in metformin-treated obeseOCs, leading to further disruption of mitochondrial function. [85], including that of complex II in OC [86]. Lastly, lysolipids were markedly decreased in the obese-versus lean-OCs, suggesting that lysolipids were being re-acylated as a means to regenerate phospholipids for membranes biosynthesis and ultimately tumor growth.…”