Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells

• DOI: 10.1172/jci.insight.98096
• Publication Date: 2018-02-07T16:01:03Z
• Authors: Yanling Wang; Haineng Xu; Tianrun Liu; Menggui Huang; Param-Puneet Butter; Chunsheng Li; Lin Zhang; Gary D. Kao; Yanqing Gong; Amit Maity; Constantinos Koum...; Yi Fan
• Keywords: Male; 0301 basic medicine; DNA Repair; Gene Expression Profiling; Nuclear Proteins; DNA-Activated Protein Kinase; Glioma; Radiation Tolerance; Genomic Instability; Acid Anhydride Hydrolases; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; DNA Repair Enzymes; Cell Line, Tumor; Neoplastic Stem Cells; Animals; Humans; Female; RNA, Small Interfering; DNA Damage

Cancer stem cells (CSCs) - known to be resistant to genotoxic radiation and chemotherapy - are fundamental to therapy failure and cancer relapse. Here, we reveal that glioma CSCs are hypersensitive to radiation, but a temporal DNA repair mechanism converts the intrinsic sensitivity to genomic instability and treatment resistance. Transcriptome analysis identifies DNA-dependent protein kinase (DNA-PK) as a predominant DNA repair enzyme in CSCs. Notably, DNA-PK activity is suppressed after irradiation when ROS induce the dissociation of DNA-PKcs with Ku70/80, resulting in delayed DNA repair and radiosensitivity; subsequently, after ROS clearance, the accumulated DNA damage and robust activation of DNA-PK induce genomic instability, facilitated by Rad50-mediated cell-cycle arrest, leading to enhanced malignancy, CSC overgrowth, and radioresistance. Finally, we show a requisite in vivo role for DNA-PK in CSC-mediated radioresistance and glioma progression. These findings identify a time-sensitive mechanism controlling CSC resistance to DNA-damaging treatments and suggest DNA-PK/Rad50 as promising targets for CSC eradication.