Journal Article

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

Mao, Wei, Dong, Pin, Yang, Jianqiang, Wu, Xiaoliang, Wang, Xing, Chen, Xinwei, Liu, Yuanyuan, Feng, Chen, Chen, Lixiao, Liu, Yuying

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/109 / 13/51 / 4-Nitroquinoline 1-oxide / 45/77 / 59/5 / 631/67/1536 / 64/60 / 692/699/67/1536 / Acetyltransferase / Angiogenesis / Antibodies / Biochemistry / Biomedical and Life Sciences / CD8 antigen / Cell Biology / Cell Culture / Head & neck cancer / Head and neck carcinoma / Immunology / Life Sciences / Lymph nodes / Lymphatic system / Lymphocytes T / MAP kinase / Membrane proteins / Metastases / Metastasis / N-Acetyltransferase / Post-transcription / RNA modification / Signal transduction / Squamous cell carcinoma / Tumor microenvironment / Tumorigenesis