NAT10 mediated mRNA acetylation modification patterns associated with colon cancer progression and microsatellite status

N4-acetylcytidine (ac4C) is one type of RNA modification found in eukaryotes. RNA acetylation modifications are gradually expanding in oncology. However, the role of RNA acetylation modifications in colorectal cancer and its association with colorectal cancer microsatellite status remain unclear. Using public databases and in vitro experiments, we verified the expression and biological function of NAT10, as the key RNA acetylation modification enzyme, in colorectal cancer. The results showed that NAT10 was highly expressed in colorectal cancer, and significantly promoted colorectal cancer cell proliferation. NAT10 was also involved in several aspects of cell homoeostasis such as ion transport, calcium-dependent phospholipid binding, and RNA stability. NAT10 expression positively correlated with immune infiltration in colorectal cancer. We further constructed a risk regression model for mRNA acetylation in colorectal cancer using acetylation-related differential genes. We found that tumour immune infiltration, microsatellite instability (MSI) proportion, tumour immune mutation burden, and patient response to immunotherapy were positively correlated with risk scores. For the first time, our study showed that the level of mRNA acetylation modification level is elevated in colorectal cancer and positively correlates with immune infiltration and microsatellite status of patients. Based on our findings, NAT10 may be a new target for colorectal cancer treatment.

N4-乙酰胞苷（ac4C）是真核生物中存在的一类RNA修饰。RNA乙酰化修饰在肿瘤学领域的相关研究正逐步拓展。然而，RNA乙酰化修饰在结直肠癌中的作用及其与结直肠癌微卫星状态的关联仍未明确。本研究借助公共数据库与体外实验，验证了关键RNA乙酰化修饰酶NAT10在结直肠癌中的表达与生物学功能。研究结果显示，NAT10在结直肠癌组织中呈高表达状态，并可显著促进结直肠癌细胞增殖。此外，NAT10还参与了细胞稳态的多个调控环节，包括离子转运、钙依赖性磷脂结合以及RNA稳定性维持。NAT10的表达水平与结直肠癌的免疫浸润程度呈正相关。本研究进一步利用乙酰化修饰相关差异基因，构建了结直肠癌mRNA乙酰化风险回归模型。研究发现，肿瘤免疫浸润程度、微卫星不稳定（microsatellite instability，MSI）比例、肿瘤免疫突变负荷以及患者对免疫治疗的响应情况均与风险评分呈正相关。本研究首次证实，结直肠癌组织中mRNA乙酰化修饰水平升高，且该水平与患者的免疫浸润程度及微卫星状态呈正相关。基于上述研究结果，NAT10或可成为结直肠癌治疗的全新靶点。