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Aberrant Methylation and Silencing of the BNIP3 Gene in Colorectal and Gastric Cancer

¹ First Department of Internal Medicine and ² Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan; ³ PRESTO, Japan Science and Technology, Kawaguchi, Japan; ⁴ Central Animal Laboratory, National Cancer Center Research Institute, Tokyo, Japan; and ⁵ Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Ube, Japan

Requests for reprints: Minoru Toyota, First Department of Internal Medicine, Sapporo Medical University, South 1,West 16, Chuo-ku, Sapporo 060-8543, Japan. Phone: 81-11-611-2111, ext. 3211; Fax: 81-11-618-3313; E-mail: mtoyota{at}sapmed.ac.jp.

BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5' CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.

Key Words: DNA methylation • epigenetics • hypoxia

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