title: Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism.
abstract: 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.
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.
authors: Paul-Joseph P
authors: PP
authors: Aspuria
authors: Department of Physiology, Michigan State University, East Lansing, MI 48824 USA.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.
authors: Sophia Y
authors: SY
authors: Lunt
authors: Systems and Synthetic Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, 41296 Sweden.
authors: Leif
authors: L
authors: Väremo
authors: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.
authors: Laurent
authors: L
authors: Vergnes
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.|Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048 USA.
authors: Maricel
authors: M
authors: Gozo
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.|Graduate Program in Biomedical Science and Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048 USA.
authors: Jessica A
authors: JA
authors: Beach
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.
authors: Brenda
authors: B
authors: Salumbides
authors: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.
authors: Karen
authors: K
authors: Reue
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.
authors: W Ruprecht
authors: WR
authors: Wiedemeyer
authors: Systems and Synthetic Biology, Department of Chemical and Biological Engineering, Chalmers University of Technology, Gothenburg, 41296 Sweden.
authors: Jens
authors: J
authors: Nielsen
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.
authors: Beth Y
authors: BY
authors: Karlan
authors: Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048 USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.
authors: Sandra
authors: S
authors: Orsulic
keywords: Carbon metabolism; EMT; Epigenetics; Ovarian cancer; SDH; Succinate dehydrogenase