title: Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.
abstract: BACKGROUND
  Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism.
  
  
  RESULTS
  Ingenuity pathway analysis of gene expression in HSulf-1 shRNA-silenced cells (Sh1 and Sh2 cells) compared to non-targeted control shRNA cells (NTC cells) and subsequent Kyoto Encyclopedia of Genes and Genomics (KEGG) database analysis showed altered metabolic pathways with changes in the lipid metabolism as one of the major pathways altered inSh1 and 2 cells. Untargeted global metabolomic profiling in these isogenic cell lines identified approximately 338 metabolites using GC/MS and LC/MS/MS platforms. Knockdown of HSulf-1 in OV202 cells induced significant changes in 156 metabolites associated with several metabolic pathways including amino acid, lipids, and nucleotides. Loss of HSulf-1 promoted overall fatty acid synthesis leading to enhance the metabolite levels of long chain, branched, and essential fatty acids along with sphingolipids. Furthermore, HSulf-1 loss induced the expression of lipogenic genes including FASN, SREBF1, PPARγ, and PLA2G3 stimulated lipid droplet accumulation. Conversely, re-expression of HSulf-1 in Sh1 cells reduced the lipid droplet formation. Additionally, HSulf-1 also enhanced CPT1A and fatty acid oxidation and augmented the protein expression of key lipolytic enzymes such as MAGL, DAGLA, HSL, and ASCL1. Overall, these findings suggest that loss of HSulf-1 by concomitantly enhancing fatty acid synthesis and oxidation confers a lipogenic phenotype leading to the metabolic alterations associated with the progression of ovarian cancer.
  
  
  CONCLUSIONS
  Taken together, these findings demonstrate that loss of HSulf-1 potentially contributes to the metabolic alterations associated with the progression of ovarian pathogenesis, specifically impacting the lipogenic phenotype of ovarian cancer cells that can be therapeutically targeted.
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Debarshi
authors.initials: D
authors.lastname: Roy
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Susmita
authors.initials: S
authors.lastname: Mondal
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Khurana
authors.affiliation: Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hoffmann
authors.affiliation: Cancer Preventive Material Development Research Center (CPMRC), College of Oriental Medicine, Kyunghee University, Seoul 130-701, Republic of Korea.
authors.forename: Deok-Beom
authors.initials: DB
authors.lastname: Jung
authors.affiliation: Cancer Preventive Material Development Research Center (CPMRC), College of Oriental Medicine, Kyunghee University, Seoul 130-701, Republic of Korea.
authors.forename: Sung H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Eduardo N
authors.initials: EN
authors.lastname: Chini
authors.affiliation: Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Juliana Camacho
authors.initials: JC
authors.lastname: Periera
authors.affiliation: Department of Cardiovascular Disease, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Folmes
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mariani
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Dowdy
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Bakkum-Gamez
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Riska
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.affiliation: Metabolon, Inc, Durham, NC 27713, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: Metabolon, Inc, Durham, NC 27713, USA.
authors.forename: Lauren N
authors.initials: LN
authors.lastname: Bell
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KN 66160, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
keywords: HSulf-1; Lipid droplets; Lipogenesis; Lipolysis; Microarray and metabolite profiling