Demethylation-linked activation of urokinase plasminogen activator is involved in progression of prostate cancer

Increased expression of urokinase plasminogen activator (uPA) has been reported in various malignancies including prostate cancer. However, the mechanism by which uPA is abnormally expressed in prostate cancer remains elusive. Here, we show that uPA is aberrantly expressed in a high percentage of human prostate cancer tissues but rarely expressed either in tumor-matched nonneoplastic adjacent tissues or benign prostatic hyperplasia samples. This aberrant expression is associated with cancer-linked demethylation of the uPA promoter. Furthermore, treatment with demethylation inhibitor S-adenosylmethionine or stable expression of uPA short hairpin RNA significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and incidence of lung metastasis in vivo. Collectively, these findings strongly suggest that DNA demethylation is a common mechanism underlying the abnormal expression of uPA and is a critical contributing factor to the malignant progression of human prostate tumors.