RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac^(4)C modification

Existing studies have underscored the pivotal role of N-acetyltransferase 10(NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma(HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1(RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6(ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac^(4)C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel t RNA-ac^(4)C modification sites, thereby providing a potent sequencing tool for tRNAac^(4)C research. Our findings expand the repertoire of tRNA ac^(4)C modifications and identify a role of tRNA ac^(4)C in the regulation of mRNA translation in HNSCC.