Repression of Na,K-ATPase β₁-Subunit by the Transcription Factor Snail in Carcinoma

The Na,K-ATPase consists of two essential α- and β-subunits and regulates the intracellular Na⁺ and K⁺ homeostasis. Although the α-subunit contains the catalytic activity, it is not active without functional β-subunit. Here, we report that poorly differentiated carcinoma cell lines derived from colon, breast, kidney, and pancreas show reduced expression of the Na,K-ATPase β₁-subunit. Decreased expression of β₁-subunit in poorly differentiated carcinoma cell lines correlated with increased expression of the transcription factor Snail known to down-regulate E-cadherin. Ectopic expression of Snail in well-differentiated epithelial cell lines reduced the protein levels of E-cadherin and β₁-subunit and induced a mesenchymal phenotype. Reduction of Snail expression in a poorly differentiated carcinoma cell line by RNA interference increased the levels of Na,K-ATPase β₁-subunit. Furthermore, Snail binds to a noncanonical E-box in the Na,K-ATPase β ₁-subunit promoter and suppresses its promoter activity. These results suggest that down-regulation of Na,K-ATPase β₁-subunit and E-cadherin by Snail are associated with events leading to epithelial to mesenchymal transition.