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

24 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

Fingerprint

Cystathionine
Glioma
Carcinogenesis
Small Interfering RNA
Growth
Messenger RNA
Putamen
Homocysteine
Subcutaneous Injections
Computational Biology
Tumor Burden
Heterografts
Vascular Endothelial Growth Factor A
Agar
Neoplasms
Gene Expression
Incidence
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Takano, N., Sarfraz, Y., Gilkes, D. M., Chaturvedi, P., Xiang, L., Suematsu, M., ... 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

Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis. / Takano, Naoharu; Sarfraz, Yasmeen; Gilkes, Daniele M.; Chaturvedi, Pallavi; Xiang, Lisha; Suematsu, Makoto; Zagzag, David; Semenza, Gregg L.

In: Molecular Cancer Research, Vol. 12, No. 10, 01.10.2014, p. 1398-1406.

Research output: Contribution to journalArticle

Takano, N, Sarfraz, Y, Gilkes, DM, Chaturvedi, P, Xiang, L, Suematsu, M, Zagzag, D & Semenza, GL 2014, 'Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis', Molecular Cancer Research, vol. 12, no. 10, pp. 1398-1406. https://doi.org/10.1158/1541-7786.MCR-14-0184
Takano N, Sarfraz Y, Gilkes DM, Chaturvedi P, Xiang L, Suematsu M et al. Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis. Molecular Cancer Research. 2014 Oct 1;12(10):1398-1406. https://doi.org/10.1158/1541-7786.MCR-14-0184
Takano, Naoharu ; Sarfraz, Yasmeen ; Gilkes, Daniele M. ; Chaturvedi, Pallavi ; Xiang, Lisha ; Suematsu, Makoto ; Zagzag, David ; Semenza, Gregg L. / Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis. In: Molecular Cancer Research. 2014 ; Vol. 12, No. 10. pp. 1398-1406.
@article{313c0938da5f44079b6cef79c3fe6959,
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.",
author = "Naoharu Takano and Yasmeen Sarfraz and Gilkes, {Daniele M.} and Pallavi Chaturvedi and Lisha Xiang and Makoto Suematsu and David Zagzag and Semenza, {Gregg L.}",
year = "2014",
month = "10",
day = "1",
doi = "10.1158/1541-7786.MCR-14-0184",
language = "English",
volume = "12",
pages = "1398--1406",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Decreased expression of cystathionine β-synthase promotes glioma tumorigenesis

AU - Takano, Naoharu

AU - Sarfraz, Yasmeen

AU - Gilkes, Daniele M.

AU - Chaturvedi, Pallavi

AU - Xiang, Lisha

AU - Suematsu, Makoto

AU - Zagzag, David

AU - Semenza, Gregg L.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84907994736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907994736&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-14-0184

DO - 10.1158/1541-7786.MCR-14-0184

M3 - Article

VL - 12

SP - 1398

EP - 1406

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 10

ER -