δ-Catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: Implications on human prostate cancer progression

delta-Catenin binds the juxtamembrane domain of E-cadherin and is known to be overexpressed in some human tumors. However, the functions of delta-catenin in epithelial cells and carcinomas remain elusive. We found that prostate cancer cells overexpressing delta-catenin show an increase in multi-layer growth in culture. In these cells, delta-catenin colocalizes with E-cadherin at the plasma membrane, and the E-cadherin processing is noticeably elevated. E-Cadherin processing induced by delta-catenin is serum-dependent and requires MMP- and PS-1/gamma-secretase-mediated activities. A deletion mutant of delta-catenin that deprives the ability of delta-catenin to bind E-cadherin or to recruit PS-1 to E-cadherin totally abolishes the delta-catenin-induced E-cadherin processing and the multi-layer growth of the cells. In addition, prostate cancer cells overexpressing delta-catenin display an elevated total p-catenin level and increase its nuclear distribution, resulting in the activation of beta-catenin/LEF-1-mediated transcription and their downstream target genes as well as androgen receptor-mediated transcription. Indeed, human prostate tumor xenograft in nude mice, which is derived from cells overexpressing delta-catenin, shows increased beta-catenin nuclear localization and more rapid growth rates. Moreover, the metastatic xenograft tumor weights positively correlate with the level of 29 kD E-cadherin fragment, and primary human prostate tumor tissues also show elevated levels of delta-catenin expression and the E-cadherin processing. Taken together, these results suggest that delta-catenin plays an important role in prostate cancer progression through inducing E-cadherin processing and thereby activating beta-catenin-mediated oncogenic signals. (C) 2012 Elsevier B.V. All rights reserved.