Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis

Naoharu Takano, Yasmeen Sarfraz, Daniele M. Gilkes, Pallavi Chaturvedi, Lisha Xiang, Makoto Suematsu, David Zagzag, Gregg L. Semenza

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1398-1406
Number of pages9
JournalMolecular Cancer Research
Volume12
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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  • Cite this

    Takano, N., Sarfraz, Y., Gilkes, D. M., Chaturvedi, P., Xiang, L., Suematsu, M., Zagzag, D., & Semenza, G. L. (2014). Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis. Molecular Cancer Research, 12(10), 1398-1406. https://doi.org/10.1158/1541-7786.MCR-14-0184