β-Galactoside α2,6-Sialyltranferase 1 Promotes Transforming Growth Factor-β-mediated Epithelial-Mesenchymal Transition

Background: Molecular mechanisms underlying the effect of sialylation on tumor progression remain unclear. Results: ST6GAL1 promoted the TGF--induced EMT through down-regulation of E-cadherin-mediated cell adhesion and up-regulation of integrin-mediated cell migration. Conclusion: Expression of ST6GAL1 is critical for sufficient induction of EMT. Significance: 2,6-Sialylation of N-glycans may play a role in EMT. -Galactoside 2,6-sialyltranferase 1 (ST6GAL1) catalyzes the addition of terminal 2,6-sialylation to N-glycans. Increased expression of ST6GAL1 has been reported in diverse carcinomas and highly correlates with tumor progression. Here, we report that St6gal1 transcription and 2,6-sialylated N-glycans are up-regulated during TGF--induced epithelial-mesenchymal transition (EMT) in GE11 cells, requiring the Sp1 element within the St6gal1 promoter. Knockdown of St6gal1 strongly suppressed TGF--induced EMT with a concomitant increase in E-cadherin expression, a major determinant of epithelial cell adherens junctions. Conversely, overexpression of ST6GAL1 increased the turnover of cell surface E-cadherin and promoted TGF--induced EMT. Overexpressing -galactoside 2,3-sialyltranferase 4 had little influence on EMT, indicating specificity for 2,6-sialylation. The basal mesenchymal phenotype of MDA-MB-231 human breast cancer cells was partially reversed by ST6GAL1 silencing. Moreover, ST6GAL1 knockdown inhibited the phosphorylation of Akt, but not Smad2, suggesting that ST6GAL1 contributes to EMT through a non-Smad signaling pathway. Taken together, our data indicate that ST6GAL1 promotes TGF--dependent EMT as well as maintenance of the mesenchymal state by growth signaling, providing a plausible mechanism whereby up-regulated ST6GAL1 may promote malignant progression.