title: Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis.
abstract: Cystathionine β-synthase (CBS) catalyzes metabolic reactions that convert homocysteine to cystathionine. To assess the role of CBS in human glioma, cells were stably transfected with lentiviral vectors encoding shRNA targeting CBS or a nontargeting control shRNA, and subclones were injected into immunodeficient mice. Interestingly, decreased CBS expression did not affect proliferation in vitro but decreased the latency period before rapid tumor xenograft growth after subcutaneous injection and increased tumor incidence and volume following orthotopic implantation into the caudate-putamen. In soft-agar colony formation assays, CBS knockdown subclones displayed increased anchorage-independent growth. Molecular analysis revealed that CBS knockdown subclones expressed higher basal levels of the transcriptional activator hypoxia-inducible factor 2α (HIF2α/EPAS1). HIF2α knockdown counteracted the effect of CBS knockdown on anchorage-independent growth. Bioinformatic analysis of mRNA expression data from human glioma specimens revealed a significant association between low expression of CBS mRNA and high expression of angiopoietin-like 4 (ANGPTL4) and VEGF transcripts, which are HIF2 target gene products that were also increased in CBS knockdown subclones. These results suggest that decreased CBS expression in glioma increases HIF2α protein levels and HIF2 target gene expression, which promotes glioma tumor formation.
  
  
  CONCLUSIONS
  CBS loss-of-function promotes glioma growth.
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.affiliation: Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Sarfraz
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, New York. Division of Neuropathology, Department of Pathology and Neurosurgery, New York University School of Medicine, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.affiliation: gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology*; D063646:Carcinogenesis / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D003541:Cystathionine beta-Synthase / Q000172:deficiency / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000201:enzymology* / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D016513:Mice, SCID; D047368:Tumor Burden; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003541:Cystathionine beta-Synthase; D000099162:Endothelial PAS Domain-Containing Protein 1