Back to Search
Start Over
FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression
- Source :
- International Journal of Oral Science, Vol 16, Iss 1, Pp 1-16 (2024)
- Publication Year :
- 2024
- Publisher :
- Nature Publishing Group, 2024.
-
Abstract
- Abstract SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.
Details
- Language :
- English
- ISSN :
- 20493169
- Volume :
- 16
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- International Journal of Oral Science
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.b06c15a9d9f84580b2f3ee8a37c412ee
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41368-024-00289-w