2. Academic Validation
  3. N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway

N4-acetylcytidine-dependent GLMP mRNA stabilization by NAT10 promotes head and neck squamous cell carcinoma metastasis and remodels tumor microenvironment through MAPK/ERK signaling pathway

  • Cell Death Dis. 2023 Nov 1;14(11):712. doi: 10.1038/s41419-023-06245-6.
Yuanyuan Liu # 1,  Xing Wang # 2 3,  Yuying Liu # 1,  Jianqiang Yang 4,  Wei Mao 1,  Chen Feng 1,  Xiaoliang Wu 5,  Xinwei Chen 6,  Lixiao Chen 7,  Pin Dong 8
Affiliations

Affiliations

  • 1 Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 2 Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330046, China.
  • 3 Centre for Medical Research and Translation, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China.
  • 4 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, School of Medicine, Atlanta, GA, 30322, USA.
  • 5 Department of Oncology, Shenzhen Hospital of Southern Medical University, Shenzhen, 510086, China.
  • 6 Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. xinwei.chen@shgh.cn.
  • 7 Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. Chenlixiao1201@163.com.
  • 8 Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. dongpin64@aliyun.com.
  • # Contributed equally.
PMID: 37914704 DOI: 10.1038/s41419-023-06245-6
Abstract

N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification that regulates in various important biological processes. However, its role in human Cancer, especially lymph node metastasis, remains largely unknown. Here, we demonstrated N-Acetyltransferase 10 (NAT10), as the only known "writer" of ac4C mRNA modification, was highly expressed in head and neck squamous cell carcinoma (HNSCC) patients with lymph node metastasis. High NAT10 levels in the lymph nodes of patients with HNSCC patients are a predictor of poor overall survival. Moreover, we found that high expression of NAT10 was positively upregulated by Nuclear Respiratory Factor 1 (NRF1) transcription factor. Gain- and loss-of-function experiments displayed that NAT10 promoted cell metastasis in mice. Mechanistically, NAT10 induced ac4C modification of Glycosylated Lysosomal Membrane Protein (GLMP) and stabilized its mRNA, which triggered the activation of the MAPK/ERK signaling pathway. Finally, the NAT10-specific inhibitor, remodelin, could inhibit HNSCC tumorigenesis in a 4-Nitroquinoline 1-oxide (4NQO)-induced murine tumor model and remodel the tumor microenvironment, including angiogenesis, CD8+ T cells and Treg recruitment. These results demonstrate that NAT10 promotes lymph node metastasis in HNSCC via ac4C-dependent stabilization of the GLMP transcript, providing a potential epitranscriptomic-targeted therapeutic strategy for HNSCC.

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