IQGAP3 interacts with Rad17 to recruit the Mre11-Rad50-Nbs1 complex and contributes to radioresistance in lung cancer

• Published in: Cancer letters 2020-11, Vol.493, p.254-265
• Main Authors: Zeng, Yulan, Jie, Xiaohua, Wu, Bian, Wu, Gang, Liu, Li, Xu, Shuangbing
• Format: Article
• Language: English
• Subjects: A549 Cells; Acid Anhydride Hydrolases - metabolism; Animals; Antibodies; Cancer therapies; Cell cycle; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell proliferation; CHK1 protein; CRISPR; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA-Binding Proteins - metabolism; Epithelial-Mesenchymal Transition; Female; Flow cytometry; Gene Deletion; Gene Expression Regulation, Neoplastic; GTPase-activating protein; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; IQGAP3; Liver cancer; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Mammals; Medical prognosis; Mesenchyme; Metastasis; Mice; Morphogenesis; MRE11 Homologue Protein - metabolism; MRE11 protein; Mre11-Rad50-Nbs1 complex; Neoplasm Transplantation; Nuclear Proteins - metabolism; Plasmids; Prognosis; Proteins; Rad17; Radiation therapy; Radiation Tolerance; Radioresistance; Signal Transduction; Tumorigenesis; Up-Regulation
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.08.042

IQ motif containing GTPase-activating protein 3 (IQGAP3) has been implicated in diverse cellular processes, including neuronal morphogenesis, cell proliferation and motility, and epithelial-mesenchymal transition. However, its role in cancer radioresistance is completely unknown. Here, we report that IQGAP3 is overproduced in lung cancer patients and correlates with poor clinical outcomes. Functionally, we demonstrate that depletion of IQGAP3 impairs oncogenesis and overcomes radioresistance in lung cancer in vitro and in vivo. Mechanistically, we uncover that IQGAP3 interacts with Rad17 and controls its expression to activate the ATM/Chk2 and ATR/Chk1 signaling pathways by recruiting the Mre11-Rad50-Nbs1 (MRN) complex in response to DNA damage. Moreover, Rad17 is identified as the major downstream effector that mediates the functions of IQGAP3 in lung cancer. Clinically, IQGAP3 overexpression positively correlates with Rad17 upregulation in human lung cancer tissues. Collectively, these data support key role for IQGAP3 in promoting lung cancer radioresistance by interacting with Rad17 and suggest that targeting IQGAP3 may be an attractive strategy for lung cancer radiotherapy. •IQGAP3 is highly expressed and correlates with poor clinical outcomes in lung cancer patients.•IQGAP3 promotes lung cancer progression and radioresistance in vitro and in vivo.•IQGAP3 interacts with Rad17 to recruit the MRN complex and activates the ATM/Chk2 and ATR/Chk1 signaling pathways.•IQGAP3 overexpression positively correlates with Rad17 upregulation in lung cancer.