Revisiting the roles of N-acetylglucosaminyltransferase III (GnT-III/MGAT3) in cancer cell behavior and cellular signaling.

Glycosylation is a common post-translational modification in mammalian cells. Abnormal glycosylation is a universal feature of cancer cells, regarded as a hallmark of cancer, and can influence tumor progression, including cell adhesion, migration, growth, differentiation, and invasion. A key change in N-glycosylation involves the modification of bisecting N-acetylglucosamine (GlcNAc), which is catalyzed by N-acetylglucosaminyltransferase III (GnT-III, encoded by the MGAT3 gene). GnT-III is widely regarded as a key glycosyltransferase in N-glycan biosynthesis. The addition of a bisecting GlcNAc prevents further processing of N-glycans, thereby blocking the synthesis of GlcNAc-branched N-glycans by N-acetylglucosaminyltransferase IV (GnT-IV) and N-acetylglucosaminyltransferase V (GnT-V). These branched N-glycans are strongly associated with cancer invasion and metastasis. For example, in many cases, integrins and E-cadherin are modified by GnT-V, which promotes cell migration and cancer invasion. In contrast, those modified by GnT-III tend to inhibit cell migration and metastasis. Recent studies also show that GnT-III expression suppresses cancer chemoresistance caused by prolonged exposure to anticancer drugs and enhances the differentiation capacity of leukemia cells. This review will discuss the roles of GnT-III in cancer cell behavior and cellular signaling, with a particular focus on some potential target proteins.