Dysregulated Epiregulin(EREG)can activate epidermal growth factor receptor(EGFR)and promote tumor progression in head and neck squamous cell carcinoma(HNSCC).However,the mechanisms underlying EREG dysregulation remain...Dysregulated Epiregulin(EREG)can activate epidermal growth factor receptor(EGFR)and promote tumor progression in head and neck squamous cell carcinoma(HNSCC).However,the mechanisms underlying EREG dysregulation remain largely unknown.Here,we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues.Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway.Of note,we found that N-glycosylation of EREG was essential for its stability,membrane location,biological function,and upregulation of its downstream target PDL1 in HNSCC.EREG was glycosylated at N47 via STT3B glycosyltransferases,whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG.Consistently,knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells.Moreover,treatment of HNSCC cells with NGI-1,an inhibitor of STT3B,blocked STT3B-mediated glycosylation of EREG,leading to its degradation and suppression of PDL1.Finally,combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo.Taken together,STT3B-mediated N-glycosylation is essential for stabilization of EREG,which mediates PDL1 upregulation and immune evasion in HNSCC.展开更多
基金supported by the Fundamental Research program funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(JYZZ233)the National Nature Science Foundation of China(grant numbers81802696,82172565)+1 种基金The CAMS Innovation Fund for Medical Sciences(CIFMS)(Project No.2019-I2M-5-037)Shanghai Clinical Research Center for Oral Diseases(19MC1910600)。
文摘Dysregulated Epiregulin(EREG)can activate epidermal growth factor receptor(EGFR)and promote tumor progression in head and neck squamous cell carcinoma(HNSCC).However,the mechanisms underlying EREG dysregulation remain largely unknown.Here,we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues.Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway.Of note,we found that N-glycosylation of EREG was essential for its stability,membrane location,biological function,and upregulation of its downstream target PDL1 in HNSCC.EREG was glycosylated at N47 via STT3B glycosyltransferases,whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG.Consistently,knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells.Moreover,treatment of HNSCC cells with NGI-1,an inhibitor of STT3B,blocked STT3B-mediated glycosylation of EREG,leading to its degradation and suppression of PDL1.Finally,combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo.Taken together,STT3B-mediated N-glycosylation is essential for stabilization of EREG,which mediates PDL1 upregulation and immune evasion in HNSCC.
