Volume 18, No 10, Oct 2008

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 18 Issue 10, October 2008: 1037-1046

ORIGINAL ARTICLES

Promoter hypomethylation regulates CD133 expression in human gliomas

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

Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-8638, Japan Correspondence: Shinya Tanaka(tanaka@med.hokudai.ac.jp)

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.

Cell Research (2008) 18:1037-1046. doi: 10.1038/cr.2008.270; published online 5 August 2008

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