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ssDNA-Binding Protein 2 Is Frequently Hypermethylated and Suppresses Cell Growth in Human Prostate Cancer

Authors' Affiliations: ¹ Division of Head and Neck Cancer Research, Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Departments of Genetics and Pathology, Portuguese Oncology Institute-Porto, Porto, Portugal; and ³ OncoMethylome Sciences S.A., Liege, Belgium

Requests for reprints: David Sidransky, Division of Head and Neck Cancer Research, Department of Otolaryngology, Johns Hopkins University, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-502-5152; Fax: 410-614-1411; E-mail: dsidrans{at}jhmi.edu.

Purpose: Prostate cancer is a major cause of cancer death among men and the development of new biomarkers is important to augment current detection approaches.

Experimental Design: We identified hypermethylation of the ssDNA-binding protein 2 (SSBP2) promoter as a potential DNA marker for human prostate cancer based on previous bioinformatics results and pharmacologic unmasking microarray. We then did quantitative methylation-specific PCR in primary prostate cancer tissues to confirm hypermethylation of the SSBP2 promoter, and analyzed its correlation with clinicopathologic data. We further examined SSBP2 expression in primary prostate cancer and studied its role in cell growth.

Results: Quantitative methylation-specific PCR results showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%) primary prostate cancers versus 0 of 23 (0%) in benign prostatic hyperplasia using a cutoff value of 120. Furthermore, we found that expression of SSBP2 was down-regulated in primary prostate cancers and cancer cell lines. Hypermethylation of the SSBP2 promoter and its expression were closely associated with higher stages of prostate cancer. Reactivation of SSBP2 expression by the demethylating agent 5-aza-2'-deoxycytidine in prostate cancer cell lines confirmed epigenetic inactivation as one major mechanism of SSBP2 regulation. Moreover, forced expression of SSBP2 inhibited prostate cancer cell proliferation in the colony formation assay and caused cell cycle arrest.

Conclusion: SSBP2 inhibits prostate cancer cell proliferation and seems to represent a novel prostate cancer–specific DNA marker, especially in high stages of human prostate cancer.