PAX2 oncogene negatively regulates the expression of the host defense peptide human beta defensin-1 in prostate cancer.
Human beta defensin-1 (hBD1) is a component of the immune system which links the innate and adaptive immune responses. We have demonstrated that hBD1 induces rapid cytolysis of prostate cancer cells and that it may also possess tumor suppressive abilities. In addition, there is a high frequency of cancer-specific loss of hBD1 expression which further suggests its potential role in tumor progression. However, the factors responsible for the loss of hBD1 expression are not known. PAX2, a transcriptional regulator normally expressed during early development, has been implicated as an oncogene in carcinomas of the kidney, prostate, breast and ovary. It is known that expression of PAX2 in these tumor cells mediates the evasion of cell death through the suppression of cell death pathways involving the p53 tumor suppressor. However, we have demonstrated that knock-down of PAX2 expression results in cell death independent of p53 status, thus suggesting that additional cell death pathways are negatively regulated by PAX2. Here we describe a novel pathway in which PAX2 represses hBD1 expression through binding of the PAX2 homeodomain to the hBD1 promoter. Furthermore, knock-down of PAX2 expression results in the re-expression of hBD1, and subsequently prostate cancer cell death. These findings are the first to demonstrate that the PAX2 oncogene suppresses hBD1 expression in cancer and further implicate PAX2 as a novel therapeutic target for prostate cancer treatment.
Bose
Sudeep K
SK
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Gibson
Willietta
W
Bullard
Rebecca S
RS
Donald
Carlton D
CD
D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009154:Mutation; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism*
C406407:DEFB1 protein, human; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; D023083:beta-Defensins