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.

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

Department of Laboratory Medicine,Huadong Hospital Affiliated to Fudan University,Shanghai 200040,China;Cancer Institute,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200032,China;Research Center on Aging and Medicine,Fudan University,Shanghai 200040,China;Shanghai Key Laboratory of Clinical Geriatric Medicine,Shanghai 200040,China;Department of Basic Science of Oncology,College of Basic Medical Sciences,Zhengzhou University,Collaborative Innovation Center of Henan Province for Cancer Chemoprevention,Zhengzhou 450001,China;School of Medicine,Southern University of Science and Technology,Shenzhen 518055,China;State Key Laboratory of Genetic Engineering,Human Phenome Institute,Institutes of Biomedical Sciences,School of Life Sciences,Zhongshan Hospital,Fudan University,Shanghai 200032,China;State Key Laboratory of Cell Differentiation and Regulation,Henan International Joint Laboratory of Pulmonary Fibrosis,Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis,College of Life Science,Institute of Biomedical Science,Henan Normal University,Xinxiang 453007,China;Department of Surgery,University of California,San Diego 92101,USA;Anticancer Inc.,San Diego 92101,USA

癌症生物学与医学（英文版）

[1]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-.Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma)[J].癌症生物学与医学（英文版）,2022(04):504-517

Overexpressed,CRLs

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