Role of C‐terminal domain of E‐cadherin in activating β‐catenin/TCF pathway in cancer cells under hypoxic conditions

Abstract

E‐cadherin expression plays a predominant role in the development and homeostasis of epithelial architecture. Down‐regulation of transmembrane protein E‐cadherin is often considered as a marker for cancer malignancy and metastasis. In this study, the effect of hypoxia on E‐cadherin expression in different cancer cell lines was analyzed. We hypothesized that down‐regulation of E‐cadherin under hypoxia would lead to transmigration of its intracellular C‐terminal fragment to the nucleus and result in activation of ß‐catenin/ TCF pathway. Treatment of A549 lung cancer, SW480 and SW620 colon cancer, T47D breast cancer, and HEK293 cells with hypoxia, 1% oxygen for periods of two, three, or four days, resulted in a significant decrease in E‐cadherin expression, Under hypoxic conditions, E‐cadherin is highly degraded resulting in the generation of multiple bands of different molecular weights depending on cells and involved proteinases. This decrease in E‐cadherin is concomitant to an increase in Snail and Slug expression, well‐known E‐cadherin suppressors. Similarly, over‐expression of Snail and Slug in cancer cells resulted in an increase in TCF activity quantified by a luciferase assays. Finally, transient transfection of cancer cells with cloned soluble C‐terminal E‐cadherin resulted in high TCF activity compared to the control. These results suggest that in normoxia, E‐cadherin neutralizes ß‐catenin and prevent it from inducing nuclear TCF activity. However, following E‐cadherin degradation, C‐terminal E‐cadherin binds ß‐catenin and translocates to the nucleus to activate TCF.