The reduction or loss of
plakoglobin expression in late-stage
bladder cancer has been correlated with poor survival where upregulation of this
catenin member by
histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of
plakoglobin in bladder
tumorigenesis following restoration, or knockdown of expression in bladder
carcinoma cell lines. Restoration of
plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of
plakoglobin in transfectants with < 1% of cells displaying detectable nuclear localisation of
plakoglobin.
siRNA knockdown experiments targeting
plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of
E-cadherin expression. In bladder cell lines expressing low levels of
plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of
plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with
plakoglobin expression in the bladder model. These results show that
plakoglobin acts as a tumour suppressor gene in bladder
carcinoma cells and the silencing of
plakoglobin gene expression in late-stage
bladder cancer is a primary event in tumour progression.