원문정보
초록
영어
The transcriptional repressor Snail plays a key role in epithelial-mesenchymal transition (EMT) by which direct repression of E-cadherin transcription. Therefore, regulation of Snail expression level in epithelial tumor cells is important not only for maintaining of epithelial homeostasis, but also for invasion and metastasis of cancer cells by the EMT program. Series of Ser imbedded in Snail are phosphorylated by GSK3 and Snail expression is dynamically regulated by Wnt signaling together with β-catenin while driving a Snail-dependent EMT program. Glucose flux through the hexosamine biosynthetic pathway (HBP) can be used for the source of O-linked β-N-acetylglucosamine(O-GlcNAc) modification on Ser and Thr residues of various nucleocytoplasmic proteins. In this study, we demonstrate that Ser112 of Snail is O-GlcNAcylated and this adjacent-site occupancy inhibits phosphorylation by GSK-3, resulting in increased Snail stability and attenuation of E-cadherin proximal promoter activity and transcription level. Furthermore, Overexpression of OGT induces in vivo invasion program of epithelial cancer cells by Snail-dependent manner. Taken together, our results indicate dynamic interplay between O-GlcNAcylation and GSK-3 phosphorylation of Snail, and our observations may provide the molecular insight of pathogenic and prognostic correlation between cancer progression and hyperglycemic condition of diabetes.