Cadherin Switch from E- to N-cadherin in Melanoma Progression is Regulated by the PI3K/PTEN Pathway Through Twist and Snail

Background: Transition of normal melanocytic cells to malignant melanoma has characteristic features of epithelial to mesenchymal transition. This includes the disruption of the adherens junctions caused by the downregulation of E-cadherin and the upregulation of N-cadherin. The cadherins have functional importance in normal skin homeostasis and melanoma development; however, the exact mechanism(s) that regulate the 'cadherin switch' are unclear.

Objectives: To determine the mechanistic role of the PI3K/PTEN pathway in regulating the change in cadherin phenotype during melanoma progression.

Methods: Using a panel of cell lines representative of the phases of melanoma progression, we determined cellular expressions of the components of the PI3K/PTEN pathway, E- and N-cadherin, and the transcriptional regulators Twist, Snail and Slug with Western blot and immunofluorescence analysis. Transcriptional regulation of E-cadherin, N-cadherin, Twist and Snail by the PI3K/PTEN pathway was confirmed using quantitative reverse transcription-polymerase chain reaction.

Results: Loss or inactivity of PTEN correlated with the switch in cadherin phenotype during melanoma progression. PTEN-null or inactive cells exhibited high levels of phosphorylated protein kinase B (PKB)/AKT (Serine 473) (PKB-Ser473-P), undetectable levels of E-cadherin and high levels of N-cadherin. Re-introduction of PTEN or treatment with the PI3K inhibitor Wortmannin resulted in the re-expression of E-cadherin and downregulation of N-cadherin. This cadherin switch was regulated at the transcriptional level by Twist and Snail which were, in turn, transcriptionally regulated by the PI3K pathway. Although E-cadherin was re-expressed, it failed to localize to the plasma membrane.

Conclusions: The PI3K/PTEN pathway transcriptionally regulates the 'cadherin switch' via transcriptional regulation of Twist and Snail but does not regulate the localization of E-cadherin to the plasma membrane.