Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma

作     者：Jingrong Xian Shiwen Wang Yanyu Jiang Lihui Li Lili Cai Ping Chen Yue Liu Xiaofei Zeng Guoan Chen Chen Ding Robert MHoffman Lijun Jia Hu Zhao Yanmei Zhang Jingrong Xian;Shiwen Wang;Yanyu Jiang;Lihui Li;Lili Cai;Ping Chen;Yue Liu;Xiaofei Zeng;Guoan Chen;Chen Ding;Robert M.Hoffman;Lijun Jia;Hu Zhao;Yanmei Zhang

作者机构：Department of Laboratory MedicineHuadong Hospital Affiliated to Fudan UniversityShanghai 200040China Cancer InstituteLonghua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Research Center on Aging and MedicineFudan UniversityShanghai 200040China Shanghai Key Laboratory of Clinical Geriatric MedicineShanghai 200040China Department of Basic Science of OncologyCollege of Basic Medical SciencesZhengzhou UniversityCollaborative Innovation Center of Henan Province for Cancer ChemopreventionZhengzhou 450001China School of MedicineSouthern University of Science and TechnologyShenzhen 518055China State Key Laboratory of Genetic EngineeringHuman Phenome InstituteInstitutes of Biomedical SciencesSchool of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China State Key Laboratory of Cell Differentiation and RegulationHenan International Joint Laboratory of Pulmonary FibrosisHenan Center for Outstanding Overseas Scientists of Pulmonary FibrosisCollege of Life ScienceInstitute of Biomedical ScienceHenan Normal UniversityXinxiang 453007China Department of SurgeryUniversity of CaliforniaSan Diego 92101USA Anticancer Inc.San Diego 92101USA 

出 版 物：《Cancer Biology & Medicine》 (癌症生物学与医学（英文版）)

年 卷 期：2022年第19卷第4期

页      面：504-517页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81602072,81902380,81820108022,and 81625018) Innovation Program of Shanghai Municipal Education Commission(Grant No.2019-01-07-00-10-E00056) Program of Shanghai Academic/Technology Research Leader(Grant No.18XD1403800) National High Technology Research and Development Program of China(Grant No.2015AA021107-019) Scientific Research Project of Shanghai Science and Technology Commission(Grant No.18411960600) Shanghai Technological Innovation Action Projects(Grant No.18411950800) Shanghai‘Rising Stars of Medical Talent’Youth Development Program,Outstanding Youth Medical Talents,2018 the Shanghai Sailing Program(Grant No.17YF1405000). 

主　　题：NEDD8 esophageal squamous cell carcinoma cullin-RING E3 ubiquitin ligases apoptosis anticancer target 

摘      要：Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target.We aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).Methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue arrays.NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms.Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways.The cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.Results:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo.Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC cells.Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC.Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.Conclusions:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.