Post-Transcriptional Regulation of Cadherin-11 Expression by GSK-3 and β-Catenin in Prostate and Breast Cancer Cells

BACKGROUND: The cell-cell adhesion molecule cadherin-11 is important in embryogenesis and bone morphogenesis, invasion of cancer cells, lymphangiogenesis, homing of cancer cells to bone, and rheumatoid arthritis. However, very little is known about the regulation of cadherin-11 expression. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that cell density and GSK-3β regulate cadherin-11 levels in cancer cells. Inactivation of GSK3β with lithium chloride or the GSK3 inhibitor BIO and GSK3β knockdown with siRNA repressed cadherin-11 mRNA and protein levels. RNA Polymerase II chromatin immunoprecipitation experiments showed that inhibition of GSK3 does not affect cadherin-11 gene transcription. Although the cadherin-11 3′UTR contains putative microRNA target sites and is regulated by Dicer, its stability is not regulated by GSK3 inhibition or density. Our data show that GSK3β regulates cadherin-11 expression in two ways: first a β-catenin-independent regulation of cadherin-11 steady state mRNA levels, and second a β-catenin-dependent effect on cadherin-11 3′UTR stability and protein translation. CONCLUSIONS: Cadherin-11 mRNA and protein levels are regulated by the activity of GSK3β and a significant degree of this regulation is exerted by the GSK3 target, β-catenin, at the level of the cadherin-11 3′UTR