title: Role of cystathionine beta synthase in lipid metabolism in ovarian cancer.
abstract: Elevated lipid metabolism is implicated in poor survival in ovarian cancer (OC) and other cancers; however, current lipogenesis-targeting strategies lack cancer cell specificity. Here, we identify a novel role of cystathionine beta-synthase (CBS), a sulphur amino acid metabolizing enzyme highly expressed in several ovarian cancer cell lines, in driving deregulated lipid metabolism in OC. We examined the role of CBS in regulation of triglycerides, cholesterol and lipogenic enzymes via the lipogenic transcription factors SREBP1 and SREBP2. CBS silencing attenuated the expression of number of key enzymes involved in lipid synthesis (FASN and ACC1). Additionally CBS abrogates lipid uptake in OC cells. Gene silencing of CBS or SREBPs abrogated cellular migration and invasion in OC, while ectopic expression of SREBPs can rescue phenotypic effects of CBS silencing by restoring cell migration and invasion. Mechanistically, CBS represses SREBP1 and SREBP2 at the transcription levels by modulating the transcription factor Sp1. We further established the roles of both CBS and SREBPs in regulating ovarian tumor growth in vivo. In orthotopic tumor models, CBS or SREBP silencing resulted in reduced tumor cells proliferation, blood vessels formation and lipid content. Hence, cancer-selective disruption of the lipid metabolism pathway is possible by targeting CBS and, at least for OC, promises a profound benefit.
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Prabir K
authors.initials: PK
authors.lastname: Chakraborty
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Xunhao
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Soumyajit Banerjee
authors.initials: SB
authors.lastname: Mustafi
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Sounik
authors.initials: S
authors.lastname: Saha
authors.affiliation: Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Dhanasekaran
authors.affiliation: Dean A. McGee Eye Institute, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Nawajes A
authors.initials: NA
authors.lastname: Mandal
authors.affiliation: Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: McMeekin
authors.affiliation: Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Resham
authors.initials: R
authors.lastname: Bhattacharya
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Priyabrata
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D064593:Heterografts; D006801:Humans; D050155:Lipogenesis; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D018919:Neovascularization, Physiologic; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D034622:RNA Interference; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*
chemical_list: C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D002784:Cholesterol; D003541:Cystathionine beta-Synthase
keywords: CBS; SREBP; lipid metabolism; ovarian cancer