MGAT3 suppresses malignant phenotypes and attenuates EGFR/AKT/ERK signaling in lung adenocarcinoma cells in association with bisecting GlcNAc remodeling

Lung adenocarcinoma (LUAD) is a leading cause of cancer mortality. Bisecting N-acetylglucosamine (bisecting GlcNAc) is a specific N-glycan modification catalyzed by MGAT3 and has been implicated in the regulation of epidermal growth factor receptor (EGFR) activity. However, the relationship between MGAT3-associated bisecting GlcNAc remodeling and EGFR signaling in LUAD remains incompletely understood. MGAT3 expression, prognostic significance, and associated pathways were analyzed using TCGA and GEO datasets. MGAT3-overexpressing H1975 cells and MGAT3-silenced H1299 cells were used for gain- and loss-of-function studies. Cell-surface PHA-E binding, proliferation, migration, invasion, apoptosis, and EGFR/AKT/ERK signaling were assessed by flow cytometry, EdU, colony-formation, wound-healing, Transwell, Annexin V/PI, and Western blot assays. Tunicamycin was used to evaluate the contribution of N-linked glycosylation. MGAT3 was downregulated in LUAD tissues and cell lines, with its lower expression associated with T stage, overall pathological stage, and shorter survival. MGAT3 overexpression increased PHA-E binding, inhibited proliferation, migration, and invasion, promoted apoptosis, and reduced EGFR phosphorylation at Tyr1068 and Tyr1173 and attenuated downstream AKT and ERK activation without altering total EGFR abundance. MGAT3 knockdown produced opposite effects. Tunicamycin partially restored EGFR, AKT, and ERK phosphorylation in MGAT3-overexpressing cells, supporting the involvement of N-linked glycosylation and a possible contribution of MGAT3-associated bisecting GlcNAc remodeling to pathway attenuation. Collectively, these findings support MGAT3 as a potential tumor suppressor and candidate prognostic biomarker in LUAD and suggest that MGAT3-associated bisecting GlcNAc remodeling may contribute to attenuation of EGFR/AKT/ERK signaling and malignant phenotypes.