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

研究成果: Article査読

37 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1398-1406
ページ数9
ジャーナルMolecular Cancer Research
12
10
DOI
出版ステータスPublished - 2014 10月 1

ASJC Scopus subject areas

  • 分子生物学
  • 腫瘍学
  • 癌研究

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