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

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-07-01 DOI:10.1038/s41368-024-00311-1
Shengming Xu, Haifeng Wang, Yu Zhu, Yong Han, Liu Liu, Xiangkai Zhang, Jingzhou Hu, Wuchang Zhang, Shengzhong Duan, Jiong Deng, Zhiyuan Zhang, Shuli Liu
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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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通过 STT3B 介导的 N-糖基化稳定 EREG 是头颈部鳞状细胞癌中 PDL1 上调和免疫逃避的关键。
表皮生长因子受体(EGFR)失调可激活表皮生长因子受体,并促进头颈部鳞状细胞癌(HNSCC)的肿瘤进展。然而,EREG失调的机制在很大程度上仍然未知。在这里,我们发现EREG失调与HNSCC组织中PDL1的增强高度相关。用EREG处理HNSCC细胞会导致PDL1通过c-myc途径上调。值得注意的是,我们发现EREG的N-糖基化对其在HNSCC中的稳定性、膜位置、生物功能及其下游靶标PDL1的上调至关重要。EREG通过STT3B糖基转移酶在N47位点进行糖基化,而N47位点的突变会减弱N-糖基化并破坏EREG的稳定性。同样,在 HNSCC 细胞中敲除 STT3B 可抑制糖基化的 EREG 并抑制 PDL1。此外,用 STT3B 的抑制剂 NGI-1 处理 HNSCC 细胞可阻断 STT3B 介导的 EREG 糖基化,导致其降解并抑制 PDL1。最后,NGI-1治疗与抗PDLl治疗相结合,可协同提高HNSCC体内免疫疗法的疗效。综上所述,STT3B介导的N-糖基化对EREG的稳定至关重要,EREG介导了HNSCC中PDL1的上调和免疫逃避。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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