RT Journal Article SR Electronic T1 Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma JF Cancer Biology & Medicine JO Cancer Biology & Medicine FD China Anti-Cancer Association SP 504 OP 517 DO 10.20892/j.issn.2095-3941.2020.0484 VO 19 IS 4 A1 Jingrong Xian A1 Shiwen Wang A1 Yanyu Jiang A1 Lihui Li A1 Lili Cai A1 Ping Chen A1 Yue Liu A1 Xiaofei Zeng A1 Guoan Chen A1 Chen Ding A1 Robert M. Hoffman A1 Lijun Jia A1 Hu Zhao A1 Yanmei Zhang YR 2022 UL http://www.cancerbiomed.org/content/19/4/504.abstract AB 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.