FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression  

作　　者：Zhonglong Liu Xiaoyan Meng Yuxin Zhang Jingjing Sun Xiao Tang Zhiyuan Zhang Liu Liu Yue He 

机构地区：[1]Department of Oral Maxillofacial&Head and Neck Oncology,Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,National Clinical Research Center for Oral Disease,Shanghai,China [2]Department of Oral Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,College of Stomatology,Shanghai Jiao Tong University,National Center for Stomatology,National Clinical Research Center for Oral Diseases,Shanghai,China [3]Department of Oral Pathology,Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,National Clinical Research Center for Oral Disease Shanghai,Shanghai,China

出　　处：《International Journal of Oral Science》2024年第2期333-348,共16页国际口腔科学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(NSFC:82173451);Project of Biobank(YBKB202105)from Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai Municipal Health Commission(No.2022LJ001);the Natural Science Foundation of Shanghai(22ZR1437600);Shanghai’s Top Priority Research Center(2022ZZ01017).

摘　　要：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.

关 键 词：ABERRANT SQUAMOUS SEMA 

分 类 号：R739.91[医药卫生—肿瘤]