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  3. Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma

Stabilization of EREG via STT3B-mediated N-glycosylation is critical for PDL1 upregulation and immune evasion in head and neck squamous cell carcinoma

  • Int J Oral Sci. 2024 Jul 1;16(1):47. doi: 10.1038/s41368-024-00311-1.
Shengming Xu # 1 2 3 4,  Haifeng Wang # 5,  Yu Zhu # 2 3 4 6,  Yong Han 1 2 4,  Liu Liu 1 2 4,  Xiangkai Zhang 1 2 4,  Jingzhou Hu 1 2 3 4,  Wuchang Zhang 2 3,  Shengzhong Duan 2 3,  Jiong Deng 7,  Zhiyuan Zhang 8 9 10 11,  Shuli Liu 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
  • 3 Laboratory of Oral Microbiota and Systemic Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China.
  • 5 Department of Stomatology, Zhuji Affiliated Hospital of Wenzhou Medical University, Zhuji, China.
  • 6 Department of Implant Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Medical Research Center, Binzhou Medical University Hospital, Binzhou, China. jiongdeng@bzmc.edu.cn.
  • 8 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Zhiyuan.Zhang@sh9hospital.org.cn.
  • 9 National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China. Zhiyuan.Zhang@sh9hospital.org.cn.
  • 10 Laboratory of Oral Microbiota and Systemic Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Zhiyuan.Zhang@sh9hospital.org.cn.
  • 11 Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China. Zhiyuan.Zhang@sh9hospital.org.cn.
  • 12 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. liushuli@shsmu.edu.cn.
  • 13 National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China. liushuli@shsmu.edu.cn.
  • 14 Laboratory of Oral Microbiota and Systemic Diseases, College of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. liushuli@shsmu.edu.cn.
  • 15 Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China. liushuli@shsmu.edu.cn.
  • # Contributed equally.
PMID: 38945975 DOI: 10.1038/s41368-024-00311-1
Abstract

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.

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