Methylation-mediated silencing of Dlg5 facilitates bladder cancer metastasis

Dlgs (Discs large homolog 5), a member of the membrane-associated guanylate kinase adaptor family of scaffolding proteins, has been shown to participate in cancer progression. However, little is known about whether abnormal expression of Dlg5 facilitates bladder cancer metastasis. In the current study we initiated a study analyzing Dlg5 expression and its roles in human bladder cancer metastasis. The expression of Dlg5 is decreased in most bladder cancer tissues compared with adjacent normal tissues, and Dlg5 expression is further downregulated in patients with muscle-invasive tumors. DNA methylation analysis showed a methylation of Dlg5 gene in bladder cancer cell lines and in bladder cancer tumors, especially in muscle-invasive tumors. Hypermethylation of Dlg5 in bladder tumors is tightly correlated with silencing of Digs expression, which is further functionally validated by demethylation analysis in bladder cancer cell lines. Knockdown of Dlg5 increases cancer cell invasion in vitro and promotes cancer metastasis in vivo. Of clinical significance, Kaplan-Meier analysis showed that downregulation of Dlg5 is significantly associated with reduced overall survival in patients with bladder cancer. Conclusion: These data suggest that inhibition of Dlg5 by DNA hypermethylation contributes to provoke invasive phenotypes in bladder tumor. (C) 2014 Elsevier Inc. All rights reserved.