Influence of the cytoplasmic domain of E-cadherin on endogenous N-cadherin expression in malignant melanoma.

E-cadherin is known to be an important molecule in epithelial-mesenchymal transition (EMT). Malignant transformation of melanocytes frequently attends with loss of E-cadherin expression and induction of expression of mesenchymal molecules like N-cadherin. The switch of the cadherin class is an interesting phenomenon of melanoma cells and in EMT in general. Therefore, we analysed the capacity of E-cadherin to regulate expression of N-cadherin in melanocytic cells. Our experiments revealed that melanoma cells downregulate endogenous N-cadherin expression after transient transfection of full-length E-cadherin, but also of the cytoplasmic domain of E-cadherin. Therefore, we concluded that the extracellular domain of E-cadherin and cell-cell contacts are not necessary for negative regulation of N-cadherin. Melanoma cells re-expressing full-length or cytoplasmatic E-cadherin have reduced NFkappaB activity in comparison to mock-transfected cells. Downregulation of NFkappaB activity, either directly or by re-expression of E-cadherin, led to a suppression of N-cadherin promoter activity and N-cadherin expression. Consequently, an NFkappaB-binding site in the N-cadherin promoter was characterized. In summary, our results suggest that N-cadherin is directly regulated by E-cadherin. Loss of E-cadherin induces NFkappaB activity and N-cadherin expression in tumorigenic EMT.