BioProject

N4-acetylcytidine (ac4C) is a posttransciptional RNA modification regulating in various important bioprocess. More...

N4-acetylcytidine (ac4C) is a posttransciptional RNA modification regulating in various important bioprocess. However, the role in human cancer, especially lymph node metastasis, remains largely unknown. Here, we showed NAT10, as the only “writer” of ac4C mRNA modification, was highly expressed in HNSCC patients with lymph node metastasis. High NAT10 levels in lymph node of HNSCC patients predicted poor overall survival. Moreover, we found the high expression of NAT10 was positively upregulated by NRF1 transcription factor. Gain and loss-of-function displayed that NAT10 promoted cell metastasis in mice. Mechanistically, NAT10 induced ac4C modification of GLMP and stabilized its mRNA, which triggered the activation of MAPK/ERK signaling pathway. Lastly, the NAT10’s specific inhibitor Remodelin could inhibit HNSCC tumorigenesis via 4-NQO-induced murine tumor model and remodel the tumor microenvironment, including angiogenesis, CD8+ T cell and Treg recruitment. These results demonstrated that NAT10 promoted lymph node metastasis of HNSCC via ac4C-dependent stabilization of GLMP transcript, providing a potential epitranscriptomic-targeted therapeutic strategy for HNSCC. Overall design: The expression and overall survival (OS) probability of NAT10 in patients with HNSCC metastases were analyzed with the GEPIA website tool and our 43 clinical samples, respectively. Gain-of-function and loss-of-function methods were envolved and a popliteal lymphatic metastasis model was constructed to investigate the functional roles of NAT10 on HNSCC cell metastasis in vitro and in vivo. The transcription factors regulated upstream of NAT10 were explored via three public website online tools. RIP, acRIP, luciferase reporter and mRNA stabilization experiments were performed to explore the epigenetic mechanisms of NAT10 in HNSCC. A 4-NQO-induced murine tumor model was further constructed to validate the effect of the inhibitor Remodelin on tumors and the tumor microenvironment. Less...