越来越多的研究表明，转录后修饰在弥漫性大 B 细胞淋巴瘤 (DLBCL) 的肿瘤发生中发挥着至关重要的作用。 N4-乙酰胞苷（ac4C）修饰是由N-乙酰转移酶10（NAT10）催化的一种新型化学修饰，可提高翻译效率和mRNA稳定性。利用GEO数据库和临床样本探讨NAT10的表达和临床价值在DLBCL中。进行 CRISPER/Cas9 介导的 NAT10 敲除以确定 NAT10 在 DLBCL 中的生物学功能。我们进行了 RNA 测序、乙酰化 RNA 免疫沉淀测序 (acRIP-seq)、LC-MS/MS、RNA 免疫沉淀 (RIP)-qPCR 和 RNA 稳定性测定，以探索 NAT10 促进 DLBCL 进展的机制。在这里，我们证明 NAT10介导的ac4C修饰调节DLBCL的发生和进展。在 DLBCL 样本中发现 N-乙酰转移酶表达失调。 NAT10的高表达与DLBCL患者的不良预后相关。 NAT10 表达的缺失抑制细胞增殖并诱导 G0/G1 期停滞。此外，NAT10 的敲除增加了 DLBCL 细胞对依鲁替尼的敏感性。 AcRIP-seq 将溶质载体家族 30 成员 9 (SLC30A9) 鉴定为 DLBCL 中 NAT10 的下游靶标。 NAT10 以 ac4C 依赖性方式调节 SLC30A9 的 mRNA 稳定性。 SLC30A9 的基因沉默通过调节 AMP 激活蛋白激酶 (AMPK) 通路的激活来抑制 DLBCL 细胞的生长。总的来说，这些发现强调了 NAT10 介导的 ac4C RNA 修饰在 DLBCL 中的重要作用，并为基于表观遗传学的新型治疗提供了见解。策略。© 2024 作者。约翰·威利出版的《临床与转化医学》

Accumulating studies suggested that posttranscriptional modifications exert a vital role in the tumorigenesis of diffuse large B-cell lymphoma (DLBCL). N4-acetylcytidine (ac4C) modification, catalyzed by the N-acetyltransferase 10 (NAT10), was a novel type of chemical modification that improves translation efficiency and mRNA stability.GEO databases and clinical samples were used to explore the expression and clinical value of NAT10 in DLBCL. CRISPER/Cas9-mediated knockout of NAT10 was performed to determine the biological functions of NAT10 in DLBCL. RNA sequencing, acetylated RNA immunoprecipitation sequencing (acRIP-seq), LC-MS/MS, RNA immunoprecipitation (RIP)-qPCR and RNA stability assays were performed to explore the mechanism by which NAT10 contributed to DLBCL progression.Here, we demonstrated that NAT10-mediated ac4C modification regulated the occurrence and progression of DLBCL. Dysregulated N-acetyltransferases expression was found in DLBCL samples. High expression of NAT10 was associated with poor prognosis of DLBCL patients. Deletion of NAT10 expression inhibited cell proliferation and induced G0/G1 phase arrest. Furthermore, knockout of NAT10 increased the sensitivity of DLBCL cells to ibrutinib. AcRIP-seq identified solute carrier family 30 member 9 (SLC30A9) as a downstream target of NAT10 in DLBCL. NAT10 regulated the mRNA stability of SLC30A9 in an ac4C-dependent manner. Genetic silencing of SLC30A9 suppressed DLBCL cell growth via regulating the activation of AMP-activated protein kinase (AMPK) pathway.Collectively, these findings highlighted the essential role of ac4C RNA modification mediated by NAT10 in DLBCL, and provided insights into novel epigenetic-based therapeutic strategies.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.