FOXA2 loss in TGF-β1-induced EMT suppresses bisecting-GlcNAc N-glycan
synthesis in lung adenocarcinoma
Abstract
Glycosylation, a significant form of post-translational modification
(PTM) in organisms, is aberrantly expressed in cancer due to altered
glycosyltransferase activity. Studies have shown specific changes in
glycan structures associated with epithelial-mesenchymal transition
(EMT) of cancer cells. This study analyzed glycans in bronchoalveolar
lavage fluid (BALF) from lung adenocarcinoma (LUAD) patients and found a
significant reduction in glycans containing the bisecting-GlcNAc
structure. Further investigation revealed that reduced expression of
β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3)
downregulates epithelial markers, promoting EMT. Additionally, we
observed a notable downregulation of both mRNA and protein expression of
Forkhead box protein A2 (FOXA2) in early-stage LUAD, with FOXA2 loss
emerging as an adverse prognostic indicator. Cellular 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.