14-3-3σ is down-regulated in human prostate cancer

The 14-3-3σ is a negative regulator of the cell cycle, which is induced by p53 in response to DNA damage. It has been characterized as an epithelium-specific marker and down-regulation of the protein has been shown in breast cancers, suggesting its tumor-suppressive activity in epithelial cells. Here we demonstrate that 14-3-3σ protein is down-regulated in human prostate cancer cell lines, LNCaP, PC3, and DU145 compared with normal prostate epithelial cells. Immunohistochemical analysis of primary prostate cells shows that the expression of 14-3-3σ protein is epithelial cell-specific. Among prostate pathological specimens, >95% of benign hyperplasia samples show significant and diffuse immunostaining of 14-3-3σ in the cytoplasm whereas <20% of carcinoma samples show positive staining. In terms of mechanisms for the down-regulation of 14-3-3σ in prostate cancer cells, hypermethylation of the gene promoter plays a causal role in LNCaP cells as 14-3-3σ mRNA level was elevated by 5-aza-2^′-deoxycytidine demethylating treatment. Intriguingly, the proteasome-mediated proteolysis is responsible for 14-3-3σ reduction in DU145 and PC3 cells, as 14-3-3σ protein expression was increased by treatment with a proteasome inhibitor MG132. Furthermore, tumor necrosis factor-related apoptosis-inducing ligand enhances 14-3-3σ gene and protein expression in DU145 and PC3 cells. These data suggest that 14-3-3σ expression is down-regulated during the neoplastic transition of prostate epithelial cells.