机构：[1]Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.[2]Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.[3]National Clinical Research Center for Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.[4]Academician Workstation, Changsha Medical University, Changsha 410219, China.[5]Department of Laboratory Medicine, National Key Laboratory of Biotherapy/ Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.四川大学华西医院[6]Tang Center for Herbal Medicine Research, University of Chicago, Chicago, IL 60637, USA.[7]Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, USA.[8]Key Laboratory of Translational Radiation Oncology, Hunan Province, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients' survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT-DNA-PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN-ATM-CHK2 signal and ATR-CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.
基金：
This work was supported by the National Key Research
and Development Program (No. 2016YFC0905000 and No. 2016YFC0905001),
National Natural Science Foundation of China (No. 81874329, No. 81573511
and No. 81472802), Hunan Science and Technology Support Program of
Hunan Province (No. 2019TJ-Q06), Innovation Driven Project of Central South
University (No. 2016CX024), Graduate Students Independent Exploration and
Innovation Project (No. 2017zzts226), and Outstanding Youth Project of Hunan
Provincial Education Department (No. 20B075)
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区生物学
小类|2 区细胞生物学
最新[2023]版：
大类|1 区生物学
小类|2 区细胞生物学
第一作者：
第一作者机构：[1]Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.[2]Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.[3]National Clinical Research Center for Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.[4]Academician Workstation, Changsha Medical University, Changsha 410219, China.
通讯作者：
通讯机构：[1]Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.[2]Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.[3]National Clinical Research Center for Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
推荐引用方式(GB/T 7714)：
Guo Zhen,Wang You-Hong,Xu Heng,et al.LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma.[J].Cell death & disease.2021,12(1):69.doi:10.1038/s41419-020-03302-2.
APA：
Guo Zhen,Wang You-Hong,Xu Heng,Yuan Chun-Su,Zhou Hong-Hao...&Zhang Wei.(2021).LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma..Cell death & disease,12,(1)
MLA：
Guo Zhen,et al."LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma.".Cell death & disease 12..1(2021):69
生物学