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FOXA2 Loss in TGF-β1-Induced EMT Suppresses Bisecting-GlcNAc N-Glycan Synthesis in Lung Adenocarcinoma
Wei Ge1,2, Shengye Wen2,3, Xiaoli Zhou1
1Department of Respiratory Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Abstract:
Glycosylation, a major posttranslational modification (PTM), is often dysregulated in cancer due to altered glycosyltransferase activity. Studies have shown specific changes in glycan structures associated with epithelial-mesenchymal transition (EMT) in cancer cells. However, the specific mechanism by which glycosyltransferases contribute to EMT remains unclear. In this study, we used bronchoalveolar lavage fluid (BALF) from lung adenocarcinoma (LUAD) patients to comparatively characterize glycopatterns and identify dysregulated glycosyltransferases in LUAD. We found a significant reduction in N-glycans containing the bisecting GlcNAc structure and confirmed by Western blot that N-acetylglucosaminyltransferase-III (MGAT3) is downregulated in LUAD. We observed a notable downregulation of both messenger RNA (mRNA) and protein expression of Forkhead box protein A2 (FOXA2) in early-stage LUAD, with FOXA2 loss emerging as an EMT promoter. Interestingly, cellular EMT models demonstrated that FOXA2 deficiency decreased MGAT3 expression during TGF-β1-driven EMT, leading to reduced levels of bisecting-GlcNAc N-glycans in LUAD cells. Our findings unveil a novel mechanism underlying the downregulation of MGAT3 and bisecting GlcNAc N-glycan expression during EMT, a process crucial for tumor metastasis.
Insights
Lung adenocarcinoma (LUAD) shows reduced bisecting N-glycans due to decreased N-acetylglucosaminyltransferase-III (MGAT3) activity. This is linked to Forkhead box protein A2 (FOXA2) loss, promoting tumor metastasis.
Area of Science:
- Oncology
- Glycobiology
- Molecular Biology
Background:
- Glycosylation, a key posttranslational modification, is frequently altered in cancer, impacting cell behavior.
- Epithelial-mesenchymal transition (EMT) in cancer is associated with specific glycan structure changes, but the underlying mechanisms involving glycosyltransferases are not fully understood.
Purpose of the Study:
- To investigate the role of glycosyltransferases in lung adenocarcinoma (LUAD) and their connection to EMT.
- To identify specific glycan alterations and dysregulated enzymes in LUAD using patient samples.
Main Methods:
- Comparative analysis of glycopatterns in bronchoalveolar lavage fluid (BALF) from LUAD patients.
- Western blot analysis to confirm the expression levels of N-acetylglucosaminyltransferase-III (MGAT3) and Forkhead box protein A2 (FOXA2).
- Utilizing cellular EMT models to study the impact of FOXA2 deficiency on MGAT3 expression and N-glycan structures.
Main Results:
- A significant reduction in N-glycans with bisecting N-acetylglucosamine (GlcNAc) was observed in LUAD.
- N-acetylglucosaminyltransferase-III (MGAT3) was found to be downregulated in LUAD.
- Forkhead box protein A2 (FOXA2) mRNA and protein expression were notably decreased in early-stage LUAD, with FOXA2 loss promoting EMT.
- FOXA2 deficiency was shown to decrease MGAT3 expression during TGF-β1-induced EMT, reducing bisecting GlcNAc N-glycans in LUAD cells.
Conclusions:
- Downregulation of MGAT3 and reduced bisecting GlcNAc N-glycans are linked to EMT in LUAD.
- FOXA2 loss is identified as a novel mechanism driving MGAT3 downregulation and subsequent reduction in bisecting GlcNAc N-glycans during EMT.
- These findings provide insights into the glycosylation changes critical for LUAD metastasis.
