APE1 regulates the transcription of urea cycle genes through stabilizing DNA G-quadruplexes in lung adenocarcinoma [CUT&Tag]

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 various cancers, including LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, correlates with poor prognosis in LUAD patients strongly. Using human LUAD cell models and a KRAS-driven genetically engineered mouse model (GEMM), we show that APE1 deletion hampers 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. Loss of APE1 disrupts the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which can be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1’s role in metabolic regulation via G4-mediated transcription, providing a potential therapeutic target LUAD patients with elevated APE1 expression.