Regulation of vascular endothelial growth factor, VEGF, gene promoter by the tumor suppressor, WT1

Understanding angiogenesis and growth control is central for elucidating prostate tumorigenesis. However, the mechanisms of activation of the angiogenic gene, vascular endothelial growth factor (VEGF) are complex and its regulation in prostate cancer is not well understood. In previous studies, VEGF expression levels were correlated with altered levels of the zinc finger transcription factor, WT1. Since the VEGF promoter has several potential WT1 binding sites and WT1 regulates many growth control genes, here we assessed whether WT1 might also regulate VEGF transcription. Using transfection and DNA binding assays, functional WT1 binding sites were localized within the proximal VEGF promoter. Transfection of the DDS-WT1 (R394W) zinc finger mutant had no significant effect on VEGF-luciferase reporter activity, suggesting that an intact zinc finger DNA binding domain was required. Interestingly, WT1-mediated regulation of VEGF reporter constructs varied in different cell types. In androgen-responsive, LNCaP prostate cancer cells, hormone treatment enhanced WT1-mediated activation of the VEGF promoter constructs. Overall, these results suggest that WT1 transcriptionally regulates VEGF through interaction of its zinc finger DNA binding domain with the proximal GC-rich VEGF promoter. These findings may shed light on the role of WT1 in angiogenesis and prostate cancer progression.