Decoding the regulatory code: O-GlcNAcylation in epithelial-mesenchymal transition (EMT)

O-linked N-acetylglucosamine (O-GlcNAc) is a monosaccharide modification occurring on serine or threonine residues of most eukaryotic proteins. Only two enzymes, O-GlcNAc transferase and O-GlcNAc hydrolase, regulate the dynamic flux of O-GlcNAc modification, rendering it extremely responsive to nutrition and stress conditions. O-GlcNAcylation stands at the center of epithelial-mesenchymal transition (EMT), sensing nutrient and stress signals to direct the transcriptional and signaling programs that enable phenotypic plasticity, thereby establishing its fundamental role in fibrosis and tumor metastasis. EMT is an essential biological event that confers mesenchymal characteristics to epithelial cells, characterized by the suppression of E-cadherin, a key epithelial adhesion molecule, and the overexpression of N-cadherin, a mesenchymal cadherin that promotes motility, or Vimentin, a mesenchymal intermediate filament protein. This review covers recent insights on the multiple canonical and non-canonical roles of O-GlcNAc, presenting O-GlcNAc cycling as a significant post-translational mechanism involved in various aspects of EMT. Furthermore, we systematically examine the functional connections between O-GlcNAcylation and EMT, focusing on identifying key O-GlcNAcylated proteins that regulate EMT and evaluating the relative contributions of transcriptional and post-translational mechanisms mediated by this modification. A comprehensive understanding of the intricate molecular circuitry governing the interplay between O-GlcNAcylation and EMT will deepen our mechanistic insights into cellular plasticity and offer novel therapeutic avenues for combating metastasis and other EMT-associated pathologies.