头颈部鳞状细胞癌
癌症研究
生物
转移
MAPK/ERK通路
癌变
下调和上调
细胞生长
癌症
细胞迁移
癌细胞
信号转导
细胞
细胞生物学
头颈部癌
生物化学
基因
遗传学
作者
Yuanyuan Liu,Xing Wang,Yuying Liu,Jianqiang Yang,Wei Mao,Feng Chen,Xiaoliang Wu,Xinwei Chen,Lixiao Chen,Peng Dong
标识
DOI:10.1038/s41419-023-06245-6
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI