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Rad9 Has a Functional Role in Human Prostate Carcinogenesis

¹ Center for Radiological Research, Columbia University, College of Physicians and Surgeons; and ² Department of Environmental Health Sciences, Columbia University, Mailman School of Public Health, New York, New York

Requests for reprints: Howard B. Lieberman, Center for Radiological Research, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032. Phone: 212-305-9241; Fax: 212-305-3229; E-mail: lieberman{at}cancercenter.columbia.edu.

Key Words: prostate cancer • Rad9 • biomarker • gene methylation • gene amplification

Prostate cancer is currently the most common type of neoplasm found in American men, other than skin cancer, and is the second leading cause of cancer death in males. Because cell cycle checkpoint proteins stabilize the genome, the relationship of one such protein, Rad9, to prostate cancer was investigated. We found that four prostate cancer cell lines (CWR22, DU145, LNCaP, and PC-3), relative to PrEC normal prostate cells, have aberrantly high levels of Rad9 protein. The 3'-end region of intron 2 of Rad9 in DU145 cells is hypermethylated at CpG islands, and treatment with 5'-aza-2'-deoxycytidine restores near-normal levels of methylation and reduces Rad9 protein abundance. Southern blot analyses indicate that PC-3 cells contain an amplified Rad9 copy number. Therefore, we provide evidence that Rad9 levels are high in prostate cancer cells due at least in part to aberrant methylation or gene amplification. The effectiveness of small interfering RNA to lower Rad9 protein levels in CWR22, DU145, and PC-3 cells correlated with reduction of tumorigenicity in nude mice, indicating that Rad9 actively contributes to the disease. Rad9 protein levels were high in 153 of 339 human prostate tumor biopsy samples examined and detectable in only 2 of 52 noncancerous prostate tissues. There was a strong correlation between Rad9 protein abundance and cancer stage. Rad9 protein level can thus provide a biomarker for advanced prostate cancer and is causally related to the disease, suggesting the potential for developing novel diagnostic, prognostic, and therapeutic tools based on detection or manipulation of Rad9 protein abundance. [Cancer Res 2008;68(5):1267–74]

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