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Human ß-Defensin-1, a Potential Chromosome 8p Tumor Suppressor: Control of Transcription and Induction of Apoptosis in Renal Cell Carcinoma

Departments of ¹ Urology and ² Pathology and ³ Winship Cancer Institute, Emory University; ⁴ Atlanta Veterans Affairs Medical Center, Atlanta, Georgia; ⁵ Department of Cell and Molecular Biology, Duke University, Durham, North Carolina; and ⁶ Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio

Requests for reprints: John A. Petros, Department of Urology, Emory University, 1365 Clifton Road, Building B4206, Atlanta, GA 30322. Phone: 404-778-4233; E-mail: jPetros{at}emory.edu.

Human ß-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at –688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at –44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2'-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression. (Cancer Res 2006; 66(17): 8542-9)

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