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

Paul-Joseph P Aspuria,Beth Y Karlan,Jens Nielsen,Jessica A Beach,Sandra Orsulic,Laurent Vergnes,Karen Reue,Brenda Salumbides,W Ruprecht Wiedemeyer,Maricel Gozo,Leif Väremo,Sophia Y Lunt

doi:10.1186/2049-3002-2-21

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.

Highlights

Succinate dehydrogenase (SDH) is a mitochondrial metabolic enzyme complex involved in both the electron transport chain and the citric acid cycle
Using a metabolomic approach to investigate the metabolic effects of decreased SDH activity, we found that Sdhb knockdown leads to altered glucose and glutamine utilization through central carbon metabolism as well as mitochondrial dysfunction
Of 211 ovarian cancer samples that had sufficient stromal and epithelial components for evaluation, seven samples exhibited significantly decreased levels of SDHB in tumor epithelia relative to tumor stroma (Additional file 3: Figure S1). These data suggest that decreased SDH activity through altered expression of SDHB may be biologically relevant in a subset of ovarian cancers

Summary

Introduction

Succinate dehydrogenase (SDH) is a mitochondrial metabolic enzyme complex involved in both the electron transport chain and the citric acid cycle. Ovarian cancer is the most lethal gynecological malignancy in the United States, resulting in approximately 22,000 new diagnoses and 14,000 deaths in 2013 [1]. EMT is a biological process that converts epithelial cells to motile, mesenchymal cells [6]. It is largely defined by the loss of plasma membrane E-cadherin and conversion from a cobblestone-like morphology to a more spindleshaped and less adherent state. It was initially characterized as a fundamental event in morphogenesis during embryonic tissue and organ development [7].

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