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 ac⁴C 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 tRNA-ac⁴C modification sites, thereby providing a potent sequencing tool for tRNA-ac⁴C research. Our findings expand the repertoire of tRNA ac⁴C modifications and identify a role of tRNA ac⁴C in the regulation of mRNA translation in HNSCC.

现有研究强调了 N-乙酰转移酶 10 (NAT10) 在各种癌症中的关键作用。然而，头颈鳞状细胞癌 (HNSCC) 中 NAT10 及其蛋白质伙伴之间的蛋白质-蛋白质相互作用的结果仍有待探索。在这项研究中，我们发现 HNSCC 中富含丝氨酸结构域 1 (RNPS1) 的 RNA 结合蛋白 (RNPS1) 显着上调，其中 RNPS1 通过 E3 泛素连接酶、含锌指 SWIM 结构域的蛋白 6 (ZSWIM6) 抑制 NAT10 的泛素化降解，通过直接的蛋白质相互作用，从而促进 HNSCC 中 NAT10 的高表达。这种上调的 NAT10 稳定性介导特定 tRNA ac ⁴ C 修饰的增强，随后促进 IL-6 信号、IL-8 信号和 PTEN 信号等通路相关基因的翻译过程，最终在调节 HNSCC 恶性进展中发挥作用。影响 HNSCC 患者的生存和预后。此外，我们率先开发了 TRMC-seq，发现了新的 tRNA-ac ⁴ C 修饰位点，从而为 tRNA-ac ⁴ C 研究提供了有效的测序工具。我们的研究结果扩展了 tRNA ac ⁴ C 修饰的范围，并确定了 tRNA ac ⁴ C 在 HNSCC mRNA 翻译调节中的作用。