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J. Biochem, 2003, Vol. 133, No. 3 303-308
© 2003 Japanese Biochemical Society

MOLECULAR BIOLOGY

Significant Reduction of WT1 Gene Expression, Possibly Due to Epigenetic Alteration in Wilms’ Tumor

Yuji Satoh1,2, Tetsuji Nakagawachi1, Hisaya Nakadate3, Yasuhiko Kaneko4, Zenjiro Masaki2, Tsunehiro Mukai1 and Hidenobu Soejima+,1

1 Division of Molecular Biology and Genetics, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501; 2 Department of Urology, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501; 3 Department of Pediatrics, Kitasato University Hospital, 1-15-1 Kitasato, Sagamihara, Kanagawa; and 4 Department of Cancer Chemotherapy, Saitama Cancer Center Hospital, 818 Komuro, Ina, Saitama 362-0806

WT1 at 11p13 is a tumor suppressor gene, an aberration of which causes Wilms’ tumor (WT). Since WT1 expression is reduced in a certain proportion of WTs and its mutation is found only in 10–20% of WTs, we examined WT1 gene silencing due to epigenetic alteration in a total of 22 WTs. WT1 expression was significantly reduced in half of WTs without any mutation in the WT1 gene itself, suggesting that the reduction of expression was possibly epigenetic. We found promoter hypermethylation in one WT with loss of heterozygosity (LOH) and showed that promoter methylation reduced reporter gene activity by a reporter assay. These data suggested that methylation was an epigenetic mechanism leading to WT1 silencing and that the expression-reduced allele by hypermethylation combined with LOH was consistent with the revised two-hit model. In addition, as the ß-catenin mutation is frequently associated with the WT1 mutation, the association of WT1 silencing with the ß-catenin mutation was also investigated. ß-catenin mutated in only one WT without WT1 silencing, suggesting that the ß-catenin mutation was not associated with the reduction of WT1 expression.

+ To whom correspondence should be addressed. Tel: +81-952-34-2264, Fax: +81-952-34-2067, E-mail: soejimah{at}post.saga-med.ac.jp


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