NAT10,即N-乙酰转移酶10,是一种在真核细胞中普遍存在的RNA修饰酶,主要负责催化RNA N4-乙酰胞嘧啶(ac4C)的生成。这种表观遗传修饰对RNA的稳定性、翻译效率以及细胞生物学过程具有重要作用。NAT10通过修饰mRNA,影响其结构和功能,进而调控基因表达和细胞行为。
在多种癌症中,NAT10的表达和活性发生显著改变,并与肿瘤的发生、发展和转移密切相关。例如,在膀胱癌中,NAT10通过增强DNA损伤修复,促进肿瘤细胞对顺铂化疗的耐药性[1]。NAT10还通过调节mRNA的乙酰化修饰,影响膀胱癌细胞的增殖、迁移、侵袭和生存能力[3]。此外,NAT10还与结直肠癌的进展相关,其通过调节KIF23 mRNA的稳定性,激活Wnt/β-catenin信号通路,促进肿瘤的生长和转移[4]。在胃癌中,NAT10通过相变调节YTHDF1剪接,促进肿瘤的进展[9]。
除了在癌症中的作用外,NAT10还参与其他重要的生物学过程。例如,在心脏重塑过程中,NAT10通过调节RNA的乙酰化修饰,影响心脏细胞的肥大和纤维化,进而影响心脏功能[2]。在巨噬细胞中,NAT10通过调节NOX2-ROS-NF-κB信号通路,影响炎症反应[5]。此外,NAT10还参与调控脂肪酸代谢,影响细胞增殖和上皮-间质转化(EMT)[6]。在血管重塑过程中,NAT10通过调节mRNA的乙酰化修饰,影响血管平滑肌细胞的表型转换,进而影响血管结构和功能[7]。在人胚胎干细胞(hESCs)中,NAT10通过调节核心多能性转录因子的乙酰化修饰,影响细胞的自我更新和分化[8]。
综上所述,NAT10是一种重要的RNA修饰酶,通过调节mRNA的乙酰化修饰,影响基因表达和细胞行为,参与多种生物学过程。在癌症、心血管疾病、炎症反应和代谢等方面发挥重要作用。因此,NAT10可能成为治疗多种疾病的新靶点。
参考文献:
1. Xie, Ruihui, Cheng, Liang, Huang, Ming, Chen, Xu, Lin, Tianxin. . NAT10 Drives Cisplatin Chemoresistance by Enhancing ac4C-Associated DNA Repair in Bladder Cancer. In Cancer research, 83, 1666-1683. doi:10.1158/0008-5472.CAN-22-2233. https://pubmed.ncbi.nlm.nih.gov/36939377/
2. Shi, Jing, Yang, Chuanxi, Zhang, Jing, Chen, Lianmin, Kong, Xiangqing. 2023. NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation. In Circulation research, 133, 989-1002. doi:10.1161/CIRCRESAHA.122.322244. https://pubmed.ncbi.nlm.nih.gov/37955115/
3. Wang, Ganping, Zhang, Ming, Zhang, Yiming, Chen, Binshen, Liu, Chunxiao. . NAT10-mediated mRNA N4-acetylcytidine modification promotes bladder cancer progression. In Clinical and translational medicine, 12, e738. doi:10.1002/ctm2.738. https://pubmed.ncbi.nlm.nih.gov/35522942/
4. Jin, Chi, Wang, Tuo, Zhang, Dongsheng, Feng, Yifei, Sun, Yueming. 2022. Acetyltransferase NAT10 regulates the Wnt/β-catenin signaling pathway to promote colorectal cancer progression via ac4C acetylation of KIF23 mRNA. In Journal of experimental & clinical cancer research : CR, 41, 345. doi:10.1186/s13046-022-02551-7. https://pubmed.ncbi.nlm.nih.gov/36522719/
5. Zhang, Zhanqi, Zhang, Yiwen, Cai, Yongjie, Feng, Zhihui, Xu, Qiong. 2023. NAT10 regulates the LPS-induced inflammatory response via the NOX2-ROS-NF-κB pathway in macrophages. In Biochimica et biophysica acta. Molecular cell research, 1870, 119521. doi:10.1016/j.bbamcr.2023.119521. https://pubmed.ncbi.nlm.nih.gov/37307924/
6. Dalhat, Mahmood Hassan, Mohammed, Mohammed Razeeth Shait, Alkhatabi, Hind Ali, Choudhry, Hani, Khan, Mohammad Imran. . NAT10: An RNA cytidine transferase regulates fatty acid metabolism in cancer cells. In Clinical and translational medicine, 12, e1045. doi:10.1002/ctm2.1045. https://pubmed.ncbi.nlm.nih.gov/36149760/
7. Yu, Cheng, Chen, Yue, Luo, Hao, Chen, Lianglong, Zeng, Chunyu. . NAT10 promotes vascular remodelling via mRNA ac4C acetylation. In European heart journal, 46, 288-304. doi:10.1093/eurheartj/ehae707. https://pubmed.ncbi.nlm.nih.gov/39453784/
8. Liu, Rucong, Wubulikasimu, Zibaguli, Cai, Runze, Zhou, Yuan, Li, Yang. . NAT10-mediated N4-acetylcytidine mRNA modification regulates self-renewal in human embryonic stem cells. In Nucleic acids research, 51, 8514-8531. doi:10.1093/nar/gkad628. https://pubmed.ncbi.nlm.nih.gov/37497776/
9. Liu, Songyi, Lin, Chunlin, Lin, Xiang, Ye, Jianxin, Zhu, Guangwei. . NAT10 Phase Separation Regulates YTHDF1 Splicing to Promote Gastric Cancer Progression. In Cancer research, 84, 3207-3222. doi:10.1158/0008-5472.CAN-23-4062. https://pubmed.ncbi.nlm.nih.gov/39024555/