Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
Int J Oral Sci. 2024 Jul 1;16(1):47. doi: 10.1038/s41368-024-00311-1.
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.
失调的表皮调节素（EREG）可激活表皮生长因子受体（EGFR），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，我们表明，失调的 EREG 与 HNSCC 组织中增强的 PDL1 高度相关。用 EREG 处理 HNSCC 细胞会通过 c-myc 途径上调 PDL1。值得注意的是，我们发现 EREG 的 N-糖基化对于其稳定性、膜定位、生物学功能以及其下游靶标 PDL1 的上调是必不可少的。通过 STT3B 糖基转移酶，EREG 在 N47 处糖基化，而 N47 位点的突变会破坏 N-糖基化并使 EREG 不稳定。一致地，STT3B 的敲低抑制了 HNSCC 细胞中糖基化的 EREG 并抑制了 PDL1。此外，用 NGI-1（STT3B 的抑制剂）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 治疗联合使用可协同增强 HNSCC 体内免疫治疗的疗效。总之，STT3B 介导的 N-糖基化对于 EREG 的稳定是必不可少的，它介导了 HNSCC 中的 PDL1 上调和免疫逃逸。
