Yu Yanhao, Cen Chaochao, Shao Zhenyu, Wang Chaohan, Wang Yiqin, Miao Zongjie, Sun Meiling, Wang Chao, Xu Qing, Liang Kaiwei, Zhou Jiaxin, Zhou Dan, Ji Hongbin, Xu Guoliang, Du Yarui
CAS Key Laboratory of Epigenetic Regulation and Intervention, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
School of Basic Medical Sciences, Wuhan University, Wuhan 430072, China.
iScience. 2025 Mar 25;28(5):112275. doi: 10.1016/j.isci.2025.112275. eCollection 2025 May 16.
Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, strongly correlates with poor prognosis in LUAD patients. Using human LUAD cell lines and a -driven mouse model, we showed that deletion hampered cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes and by modulating the presence of G-quadruplex (G4) structures in their promoter regions. APE1 loss disrupted the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which could be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1's role in transcriptional regulation of urea cycle metabolic reprogramming via G4 structure, providing a potential therapeutic target LUAD patients with elevated APE1 expression.
肺腺癌（LUAD）仍然是全球癌症死亡的主要原因。脱嘌呤/脱嘧啶核酸内切酶1（APE1）是一种对DNA修复和氧化还原信号传导至关重要的酶，在LUAD中显著上调。在这里，我们揭示了APE1扩增，主要通过等位基因重复，与LUAD患者的不良预后密切相关。使用人LUAD细胞系和α驱动的小鼠模型，我们表明APE1缺失阻碍了细胞增殖和肿瘤生长，突出了其在肿瘤发生中的作用。从机制上讲，APE1通过调节尿素循环基因和的启动子区域中G-四链体（G4）结构的存在来促进其转录。APE1缺失破坏了尿素循环和嘧啶代谢，诱导代谢重编程和生长停滞，这可以通过CPS1或嘧啶恢复来挽救。这些发现揭示了APE1通过G4结构在尿素循环代谢重编程的转录调控中的作用，为APE1表达升高的LUAD患者提供了一个潜在的治疗靶点。
