APE1 promotes lung adenocarcinoma through G4-mediated transcriptional reprogramming of urea cycle metabolism
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 <i>KRAS</i>-driven mouse model, we showed that <i>APE1</i> deletion hampered cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes <i>CPS1</i> and <i>ARG2</i> 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.
Authors
- Jiaxin Zhou (ORCID: https://orcid.org/0000-0002-5172-3466)
- Guoliang Xu (ORCID: https://orcid.org/0000-0002-3240-3141)
- Zeyu Miao (ORCID: https://orcid.org/0009-0003-5889-1002)
- Meiling Sun (ORCID: https://orcid.org/0000-0002-5265-0756)
- Dan Zhou (ORCID: https://orcid.org/0000-0002-0674-708X)
- Kaiwei Liang (ORCID: https://orcid.org/0000-0002-6021-353X)
- Chao Wang (ORCID: https://orcid.org/0000-0002-9165-7758)
- Cheng Wang (ORCID: https://orcid.org/0000-0001-5850-4533)
- Yiqin Wang (ORCID: https://orcid.org/0000-0001-7806-992X)
- Yarui Du
- Yiheng Yu (ORCID: https://orcid.org/0009-0009-5679-6320)
- Hongbin Ji (ORCID: https://orcid.org/0000-0003-0891-6390)
- Q. N. Xu (ORCID: https://orcid.org/0000-0001-9893-8766)
- Chaochao Cen
- Zhenyu Shao
Institutions
- Shanghai Medical College of Fudan University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wuhan University (CN)
- Center for Excellence in Molecular Cell Science (CN)
Publication Details
- Journal
- iScience
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1016/j.isci.2025.112275
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Science and Technology Commission of Shanghai Municipality
- Sino-Danish Center