δ-Catenin promotes prostate cancer cell growth and progression by altering cell cycle and survival gene profiles

Background: delta-Catenin is a unique member of delta-catenin/armadillo domain superfamily proteins and its primary expression is restricted to the brain. However, delta-catenin is upregulated in human prostatic adenocarcinomas, although the effects of delta-catenin overexpression in prostate cancer are unclear. We hypothesized that delta-catenin plays a direct role in prostate cancer progression by altering gene profiles of cell cycle regulation and cell survival. Results: We employed gene transfection and small interfering RNA to demonstrate that increased delta-catenin expression promoted, whereas its knockdown suppressed prostate cancer cell viability. delta-Catenin promoted prostate cancer cell colony formation in soft agar as well as tumor xenograft growth in nude mice. Deletion of either the amino-terminal or carboxyl-terminal sequences outside the armadillo domains abolished the tumor promoting effects of delta-catenin. Quantitative RT2 Profilerâ„¢ PCR Arrays demonstrated gene alterations involved in cell cycle and survival regulation. delta-Catenin overexpression upregulated cyclin D1 and cdc34, increased phosphorylated histone-H3, and promoted the entry of mitosis. In addition, delta-catenin overexpression resulted in increased expression of cell survival genes Bcl-2 and survivin while reducing the cell cycle inhibitor p21Cip1. Conclusion: Taken together, our studies suggest that at least one consequence of an increased expression of delta-catenin in human prostate cancer is the alteration of cell cycle and survival gene profiles, thereby promoting tumor progression. Originally published Molecular Cancer, Vol. 8, No. 19, Mar 200

Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer

<p>Abstract</p> <p>Background</p> <p>Neuronal synaptic junction protein δ-catenin (<it>CTNND2</it>) is often overexpressed in prostatic adenocarcinomas but the mechanisms of its activation are unknown. To address this question, we studied the hypothesis that Hes1, human homolog of <it>Drosophila </it>Hairy and enhancer of split (Hes) 1, is a transcriptional repressor of δ-catenin expression and plays an important role in molecular carcinogenesis.</p> <p>Results</p> <p>We identified that, using a <it>δ-catenin </it>promoter reporter assay, Hes1, but not its inactive mutant, significantly repressed the upregulation of δ-catenin-luciferase activities induced by E2F1. Hes1 binds directly to the E-boxes on <it>δ-catenin </it>promoter and can reduce the expression of δ-catenin in prostate cancer cells. In prostate cancer CWR22-Rv1 and PC3 cell lines, which showed distinct δ-catenin overexpression, E2F1 and Hes1 expression pattern was altered. The suppression of Hes1 expression, either by γ-secretase inhibitors or by siRNA against Hes1, increased δ-catenin expression. γ-Secretase inhibition delayed S/G2-phase transition during cell cycle progression and induced cell shape changes to extend cellular processes in prostate cancer cells. In neuroendocrine prostate cancer mouse model derived allograft NE-10 tumors, δ-catenin showed an increased expression while Hes1 expression was diminished. Furthermore, <it>E2F1 </it>transcription was very high in subgroup of NE-10 tumors in which <it>Hes1 </it>still displayed residual expression, while its expression was only moderately increased in NE-10 tumors where Hes1 expression was completely suppressed.</p> <p>Conclusion</p> <p>These studies support coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression.</p

E-Cadherin negatively modulates delta-catenin-induced morphological changes and RhoA activity reduction by competing with p190RhoGEF for delta-catenin

δ-Catenin is a member of the p120-catenin subfamily of armadillo proteins. Here we describe istinctive features of δ-catenin localization and its association with E-cadherin in HEK293 epithelial ells. In HEK293 cells maintained in low cell densities approximately 15% of cells overexpressing ´-catenin showed dendrite-like process formation but there was no detectable change in RhoA ctivity. In addition δ-catenin was localized mainly in the cytoplasm and was associated with 190RhoGEF. However at high cell densities δ-catenin localization was shifted to the plasma embrane. The association of δ-catenin with E-cadherin was strengthened whereas its interaction ith p190RhoGEF was weakened. In mouse embryonic fibroblast cell ectopic expression of Ecadherin ecreased the effect of δ-catenin on the reduction of RhoA activity as well as on dendritelike rocess formation. These results suggest that δ-catenin is more dominantly bound to E-cadherin han to p190RhoGEF and that δ-catenin’s function is dependent on its cellular binding partner. Originally published Biochem Biophys Res Commun Vol. 377 No. 2 Dec 200

Molecular Cancer BioMed Central

δ-Catenin promotes prostate cancer cell growth and progression by altering cell cycle and survival gene profile

WNK4 phosphorylates ser206 of claudin-7 and promotes paracellular Cl− permeability

AbstractMutations in WNK4 have been linked to hypertension in PHAII. Paracellular ion transport has been reported to be involved in this disease process; however, the specific molecular target has not been identified. In this study, we found that TJ protein claudin-7 and WNK4 were partially co-localized in renal tubules of rat kidney and co-immunoprecipitated in kidney epithelial cells. The wild-type and PHAII-causing mutant, but not the kinase-dead mutant, phosphorylated claudin-7. We have identified ser206 in the COOH-terminus of claudin-7 as a putative phosphorylation site for WNK4. More importantly, disease-causing mutant enhanced claudin-7 phosphorylation and significantly increased paracellular permeability to Cl−

Presenilin-1 inhibits delta-catenin-induced cellular branching and promotes delta-catenin processing and turnover

Although delta-catenin/neural plakophilin-related armadillo protein (NPRAP) was reported to interact with presenilin-1 (PS-1), the effects of PS-1 on delta-catenin have not been established. In this study, we report that overexpression of PS-1 inhibits the delta-catenin-induced dendrite-like morphological changes in NIH 3T3 cells and promotes delta-catenin processing and turnover. The effects of PS-1 on endogenous delta-catenin processing were confirmed in hippocampal neurons overexpressing PS-1, as well as in the transgenic mice expressing the disease-causing mutant PS-1 (M146V). In addition, disease-causing mutant PS-1 (M146V and L286V) enhanced delta-catenin processing, whereas PS-1/gamma-secretase inhibitors could block the formation of processed forms of delta-catenin. Together, our findings suggest that PS-1 can affect delta-catenin-induced morphogenesis possibly through the regulation of its processing and stability. Originally published Biochem Biophys Res Commun, Vol. 351, No. 4, Dec 200

Bromopropane Compounds Increase the Stemness of Colorectal Cancer Cells

Bromopropane (BP) compounds, including 1-bromopropane, 2-bromopropane, and 1,2-dibromopropane, are used in industry for various purposes, and their deleterious effects on human health are becoming known. In this study, we examined the effects of BP compounds on the stemness of colorectal cancer cells. At low, non-cytotoxic concentrations, BP compounds significantly increased spheroid formation in CSC221, DLD1, Caco2, and HT29 cells. In addition, the levels of cancer stem cell markers, such as aldehyde dehydrogenase-1, cluster of differentiation 133 (CD133), CD44, Lgr5, Musashi-1, Ephrin receptor, and Bmi-1 increased after exposure to BP compounds. BP compounds increased the transcriptional activity of the TOPflash and glioma-associated oncogene homolog zinc finger protein (Gli) promoters in reporter assays and increased the expression of Gli-1, Gli-2, Smoothened (SMO), and β-catenin by RT-PCR. These results demonstrate for the first time that BP compounds have the potential to promote cancer stemness