APE1 promotes lung adenocarcinoma through G4-mediated transcriptional reprogramming of urea cycle metabolism
Yanhao Yu,
Chaochao Cen,
Zhenyu Shao,
Chaohan Wang,
Yiqin Wang,
Zongjie Miao,
Meiling Sun,
Chao Wang,
Qing Xu,
Kaiwei Liang,
Jiaxin Zhou,
Dan Zhou,
Hongbin Ji,
Guoliang Xu,
Yarui Du
Affiliations
Yanhao Yu
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
Chaochao Cen
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
Zhenyu Shao
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
Chaohan Wang
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
Yiqin Wang
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
Zongjie Miao
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
Meiling Sun
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
Chao Wang
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
Qing Xu
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
Kaiwei Liang
School of Basic Medical Sciences, Wuhan University, Wuhan 430072, China
Jiaxin Zhou
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
Dan Zhou
Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) & Zhongshan-Xuhui Hospital, Medical College of Fudan University, Shanghai 200032, China
Hongbin Ji
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
Guoliang Xu
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; Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) & Zhongshan-Xuhui Hospital, Medical College of Fudan University, Shanghai 200032, China
Yarui Du
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; Corresponding author
Summary: 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 KRAS-driven mouse model, we showed that APE1 deletion hampered cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 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.
