title: The neddylation-cullin 2-RBX1 E3 ligase axis targets tumor suppressor RhoB for degradation in liver cancer.
abstract: The neddylation-cullin-RING E3 ligase (CRL) pathway has recently been identified as a potential oncogenic event and attractive anticancer target; however, its underlying mechanisms have not been well elucidated. In this study, RhoB, a well known tumor suppressor, was identified and validated with an iTRAQ-based quantitative proteomic approach as a new target of this pathway in liver cancer cells. Specifically, cullin 2-RBX1 E3 ligase, which requires NEDD8 conjugation for its activation, interacted with RhoB and promoted its ubiquitination and degradation. In human liver cancer tissues, the neddylation-CRL pathway was overactivated and reversely correlated with RhoB levels. Moreover, RhoB accumulation upon inhibition of the neddylation-CRL pathway for anticancer therapy contributed to the induction of tumor suppressors p21 and p27, apoptosis, and growth suppression. Our findings highlight the degradation of RhoB via the neddylation-CRL pathway as an important molecular event that drives liver carcinogenesis and RhoB itself as a pivotal effector for anticancer therapy targeting this oncogenic pathway.
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and ¶Institutes of Biomedical Sciences, Shanghai Medical College, and.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and.
authors.forename: Lihui
authors.initials: L
authors.lastname: Li
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and.
authors.forename: Guangyang
authors.initials: G
authors.lastname: Yu
authors.affiliation: ‖State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China; **National Engineering Research Center for Protein Drugs, Beijing 102206, China;
authors.forename: Wantao
authors.initials: W
authors.lastname: Ying
authors.affiliation: ‡‡Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: ‖State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China; **National Engineering Research Center for Protein Drugs, Beijing 102206, China;
authors.forename: Xianyu
authors.initials: X
authors.lastname: Li
authors.affiliation: ‖State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China; **National Engineering Research Center for Protein Drugs, Beijing 102206, China;
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and.
authors.forename: Dongping
authors.initials: D
authors.lastname: Wei
authors.affiliation: §§Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
authors.forename: Shengzhong
authors.initials: S
authors.lastname: Duan
authors.affiliation: ¶Institutes of Biomedical Sciences, Shanghai Medical College, and.
authors.forename: Qunying
authors.initials: Q
authors.lastname: Lei
authors.affiliation: ¶¶Center for Bioinformatics and Computational Biology and Institute of Biomedical Sciences, School of Life Science, East China Normal University, Shanghai 200241, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: ¶¶Center for Bioinformatics and Computational Biology and Institute of Biomedical Sciences, School of Life Science, East China Normal University, Shanghai 200241, China.
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.affiliation: ‖State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China; **National Engineering Research Center for Protein Drugs, Beijing 102206, China;
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Qian
authors.affiliation: ‖State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China; **National Engineering Research Center for Protein Drugs, Beijing 102206, China;
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and ljjia@fudan.edu.cn.
authors.forename: Lijun
authors.initials: L
authors.lastname: Jia
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism*; D045325:HCT116 Cells; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D061986:MCF-7 Cells; D000075687:NEDD8 Protein; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D014452:Ubiquitins / Q000378:metabolism*; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
chemical_list: C105153:CUL2 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C479529:RBX1 protein, human; D014452:Ubiquitins; D020743:rhoB GTP-Binding Protein