Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription

TLDR

The study demonstrates that glycogen synthase kinase‑3 activity is required to preserve epithelial architecture. Inhibiting GSK‑3 activity or knocking it down in normal breast and skin epithelial cells decreases E‑cadherin expression and induces a mesenchymal morphology characteristic of EMT. GSK‑3 inhibition activates Snail transcription, a process mediated by NFκB suppression, thereby promoting EMT and highlighting the kinase’s essential role in preventing mesenchymal transition.

Abstract

We report that the activity of glycogen synthase kinase-3 (GSK-3) is necessary for the maintenance of the epithelial architecture. Pharmacological inhibition of its activity or reducing its expression using small interfering RNAs in normal breast and skin epithelial cells results in a reduction of E-cadherin expression and a more mesenchymal morphology, both of which are features associated with an epithelial–mesenchymal transition (EMT). Importantly, GSK-3 inhibition also stimulates the transcription of Snail, a repressor of E-cadherin and an inducer of the EMT. We identify NFκB as a transcription factor inhibited by GSK-3 in epithelial cells that is relevant for Snail expression. These findings indicate that epithelial cells must sustain activation of a specific kinase to impede a mesenchymal transition.