Significant Reduction of <i>WT1</i> Gene Expression, Possibly Due to Epigenetic Alteration in Wilms' Tumor
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<i>WT1</i> at 11p13 is a tumor suppressor gene, an aberration of which causes Wilms' tumor (WT). Since <i>WT1</i> expression is reduced in a certain poroportion of WTs and its mutation is found only in 10-20% of WTs, we examined <i>WT1</i> gene silencing due to epigenetic alteration in a total of 22 WTs. <i>WT1</i> expression was significantly reduced in half of WTs without any mutation in the <i>WT1</i> 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 <i>WT1</i> silencing and that the expression-reduced allele by hypermethylation combined with LOH was consistent with the revised twohit model. In addition, as the β-<i>catenin</i> mutation is frequently associated with the <i>WT1</i> mutation, the association of <i>WT1</i> silencing with the β-<i>catenin</i> mutation was also investigated. β-<i>catenin</i> mutated in only one WT without <i>WT1</i> silencing, suggesting that the β-<i>catenin</i> mutation was not associated with the reduction of <i>WT1</i> expression.
- The Journal of Biochemistry
The Journal of Biochemistry 133(3), 303-308, 2003
The Japanese Biochemical Society