Promoter hypomethylation regulates CD133 expression in human gliomas

Kouichi Tabu, Ken Sasai, Taichi Kimura, Lei Wang, Eiko Aoyanagi, Shinji Kohsaka, Mishie Tanino, Hiroshi Nishihara, Shinya Tanaka

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Brain tumor-initiating cells (BTICs) have been enriched using antibodies against the cell surface protein CD133; however, the biological relevance and the regulatory mechanism of CD133 expression in human gliomas are not yet understood. In this study, we initially demonstrated that CD133 was overexpressed in high-grade human glioblastomas where CD133-positive cells were focally observed as a micro-cluster. In addition, CD133 transcripts with exon 1A, 1B, or 1C were predominantly expressed in glioblastomas. To elucidate the mechanism regulating this aberrant expression of CD133, three proximal promoters (P1, P2, and P3) containing a CpG island were isolated. In U251MG and T98G glioblastoma cells, the P1 region flanking exon 1A exhibited the highest activity among the three promoters, and this activity was significantly inactivated by in vitro methylation. After treatment with the demethylating agent 5-azacytidine and/or the histone deacetylase inhibitor valproic acid, the expression level of CD133 mRNA was significantly restored in glioma cells. Importantly, hypomethylation of CpG sites within the P1, P2, and P3 regions was observed by bisulfite sequencing in human glioblastoma tissues with abundant CD133 mRNA. Taken together, our results indicate that DNA hypomethylation is an important determinant of CD133 expression in glioblastomas, and this epigenetic event may be associated with the development of BTICs expressing CD133.

Original languageEnglish
Pages (from-to)1037-1046
Number of pages10
JournalCell Research
Volume18
Issue number10
DOIs
Publication statusPublished - 2008 Oct 1
Externally publishedYes

Fingerprint

Glioblastoma
Glioma
Neoplastic Stem Cells
Brain Neoplasms
Exons
Azacitidine
Messenger RNA
CpG Islands
Histone Deacetylase Inhibitors
Valproic Acid
Epigenomics
Methylation
Membrane Proteins
Antibodies
DNA

Keywords

  • CD133
  • Glioma
  • Hypomethylation
  • Promoter

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Tabu, K., Sasai, K., Kimura, T., Wang, L., Aoyanagi, E., Kohsaka, S., ... Tanaka, S. (2008). Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Research, 18(10), 1037-1046. https://doi.org/10.1038/cr.2008.270

Promoter hypomethylation regulates CD133 expression in human gliomas. / Tabu, Kouichi; Sasai, Ken; Kimura, Taichi; Wang, Lei; Aoyanagi, Eiko; Kohsaka, Shinji; Tanino, Mishie; Nishihara, Hiroshi; Tanaka, Shinya.

In: Cell Research, Vol. 18, No. 10, 01.10.2008, p. 1037-1046.

Research output: Contribution to journalArticle

Tabu, K, Sasai, K, Kimura, T, Wang, L, Aoyanagi, E, Kohsaka, S, Tanino, M, Nishihara, H & Tanaka, S 2008, 'Promoter hypomethylation regulates CD133 expression in human gliomas', Cell Research, vol. 18, no. 10, pp. 1037-1046. https://doi.org/10.1038/cr.2008.270
Tabu K, Sasai K, Kimura T, Wang L, Aoyanagi E, Kohsaka S et al. Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Research. 2008 Oct 1;18(10):1037-1046. https://doi.org/10.1038/cr.2008.270
Tabu, Kouichi ; Sasai, Ken ; Kimura, Taichi ; Wang, Lei ; Aoyanagi, Eiko ; Kohsaka, Shinji ; Tanino, Mishie ; Nishihara, Hiroshi ; Tanaka, Shinya. / Promoter hypomethylation regulates CD133 expression in human gliomas. In: Cell Research. 2008 ; Vol. 18, No. 10. pp. 1037-1046.
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