Targeted inhibition of acidic nucleoplasmic DNA-binding protein 1 enhances radiosensitivity of non-small cell lung cancer

• Published in: Cancer letters Vol. 530; pp. 100 - 109
• Main Authors: Gou, Wenfeng, Yu, Xiaojun, Wu, Shaohua, Wu, Hongying, Chang, Huajie, Chen, Leyuan, Wei, Huiqiang, Bi, Changfen, Ning, Hongxin, Wu, Yingliang, Hou, Wenbin, Zuo, Daiying, Li, Yiliang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.04.2022; Elsevier Limited
• Subjects: A549 Cells; AND-1; Apoptosis; Apoptosis - genetics; Binding sites; Cancer therapies; Carcinoma, Non-Small-Cell Lung - genetics; Cell culture; Cell cycle; Cell cycle arrest; Cell Cycle Checkpoints - genetics; Cell Line; Cell Line, Tumor; Cell Proliferation - genetics; Comet assay; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA Damage - genetics; DNA damage Repair; DNA repair; DNA Repair - genetics; DNA-binding protein; DNA-Binding Proteins - genetics; Drug dosages; Flow cytometry; G2 Phase Cell Cycle Checkpoints - genetics; Gene expression; Homologous recombination; Human Umbilical Vein Endothelial Cells; Humans; Immunofluorescence; Lung cancer; Lung Neoplasms - genetics; Non-small cell lung carcinoma; NSCLC; Proteins; Radiation; Radiation therapy; Radiation Tolerance - genetics; Radiosensitivity; Radiosensitization; Radiosensitizers; Signal transduction; siRNA; Small cell lung carcinoma; Tumors; Xenografts; United States > US; China; DSBs; DEGs; Radiosensitivity; AND-1; NSCLC; Cell cycle arrest; CtIP; HR; ATM; DNA damage Repair; ATR
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.01.020

Acidic nucleoplasmic DNA binding protein 1 (AND-1, also known as WD repeat and HMG-box DNA-binding protein 1, WDHD1) plays an important role in DNA replication and repair, but the relationship between AND-1 and radiosensitivity is not well understood. This research explored the impact of AND-1 on the radiosensitivity of non-small cell lung cancer (NSCLC) for the first time. NSCLC cells were treated with AND-1 siRNA or a new AND-1 inhibitor, CH-3, and clonogenic survival assay was used to characterize cell radiosensitivity. Cell cycle and apoptosis were examined by flow cytometry. DNA damage was detected by comet assay, immunofluorescence, and homologous recombination (HR) repair assay. Finally, the radiosensitization effect of CH-3 was investigated in vivo in a xenograft tumor model. The results showed that AND-1 inhibition significantly increased the radiosensitivity of NSCLC cells. Mechanistically, AND-1 inhibitor (CH-3) induced G2/M phase arrest by regulating the ATM signaling pathway and enhanced irradiation-induced DNA damage by inhibiting the DNA HR repair pathway. CH-3 enhanced the radiosensitivity of NSCLC cells in vivo. The development of radiosensitizers that target AND-1 may provide an alternative strategy to inhibit NSCLC. •Inhibition of AND-1 can significantly enhance the radiosensitivity of NSCLC cells.•CH3 is a specific AND-1 inhibitor that reduces the expression of AND-1.•CH3 enhances the radiation-induced G2/M phase arrest by the ATM/CDC25C pathway.•CH3 enhances the radiosensitivity of NSCLC in an apoptosis-independent manner.