1. ¹Winship Cancer Institute and Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA, USA
2. ²Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA
3. ³Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
4. ⁴Atlanta VA Medical Center, Decatur, GA, USA
5. ⁵Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA
6. ⁶Department of Urology, University of Washington, Seattle, WA, USA
7. ⁷INSERM U482, Hôpital St-Antoine, Paris, France
8. ⁸Department of Genetics and Cell Biology, Nankai University College of Life Sciences, Tianjin, China

Correspondence: Dr JT Dong, Winship Cancer Institute, Emory University School of Medicine, 1365 Clifton Road, Room C4080, Atlanta, GA 30322, USA. E-mail: jdong2@emory.edu

Received 27 April 2006; Revised 26 June 2006; Accepted 30 June 2006; Published online 2 October 2006.

Abstract

The gene for E3 ubiquitin ligase WWP1 is located at 8q21, a region frequently amplified in human cancers, including prostate cancer. Recent studies have shown that WWP1 negatively regulates the TGF tumor suppressor pathway by inactivating its molecular components, including Smad2, Smad4 and TR1. These findings suggest an oncogenic role of WWP1 in carcinogenesis, but direct supporting evidence has been lacking. In this study, we examined WWP1 for gene dosage, mRNA expression, mutation and functions in a number of human prostate cancer samples. We found that the WWP1 gene had copy number gain in 15 of 34 (44%) xenografts and cell lines from prostate cancer and 15 of 49 (31%) clinical prostate cancer samples. Consistently, WWP1 was overexpressed in 60% of xenografts and cell lines from prostate cancer. Mutation of WWP1 occurred infrequently in prostate cancer. Functionally, WWP1 overexpression promoted colony formation in the 22Rv1 prostate cancer cell line. In PC-3 prostate cancer cells, WWP1 knockdown significantly suppressed cell proliferation and enhanced TGF-mediated growth inhibition. These findings suggest that WWP1 is an oncogene that undergoes genomic amplification at 8q21 in human prostate cancer, and WWP1 overexpression is a common mechanism involved in the inactivation of TGF function in human cancer.