Ubiquitin specific protease 18 (Usp18) is a WT1 transcriptional target

Wilms tumor gene WT1 encodes a zinc finger-containing transcription factor which is required for renal development. Mutations in WT1 are observed in 20% of Wilms tumors (a pediatric kidney cancer), but the in vivo WT1 targets and associated molecular pathways involved in the etiology of Wilms tumor are still elusive. To identify WT1 targets we performed genome-wide comprehensive expression profiling using Affymetrix Gene Chip Mouse Genome 430 2.0 Arrays, comparing E13.5 mouse kidneys in which Wt1 had been somatically ablated with littermate controls. We identified Usp18 as the most differentially expressed gene in mutant kidney. Using tetracycline inducible cells we demonstrated a repressive effect of WT1 on USP18 expression. Conversely, knockdown of WT1 led to the upregulation of Usp18. Furthermore, direct binding of WT1 to the Usp18 promoter was demonstrated by ChIP assay. Overexpression of USP18 in murine and human cell lines resulted in cell proliferation. Additionally, Usp18 upregulation was observed in a mouse model of Wilms tumor. Taken together our data demonstrate that Usp18 is a transcriptional target of WT1 and suggest that increased expression of USP18 following WT1 loss contributes to Wilms tumorigenesis.

► Wt1 is a transcriptional repressor of Usp18 gene. ► Usp18 expression is increased in the Wt1 mutant mouse kidney. ► ChIP analyses demonstrate that WT1 binds to and represses USP18 expression. ► Usp18 expression is upregulated in mouse Wilms tumors with Wt1 ablation.