title: Jab1/CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Aberrant expression of Jab1/CSN5, a negative regulator of the cell-cycle inhibitor p27, is correlated with reduced p27 expression and associated with advanced tumor stage and poor prognosis in several human cancers. In this study, we examined the functional relationship between Jab1 and p27 protein expression in NPC. Immunohistochemical analysis showed an inverse association between Jab1 and p27 in NPC tissue samples, and overexpression of Jab1 correlated with poor survival in patients with NPC. Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome-dependent manner. Knockdown of Jab1 resulted in a remarkable increase in p27 levels and inhibition of cell proliferation, indicating that Jab1 targets p27 for degradation, thereby controlling its stability. Jab1 depletion also enhanced the antitumor effects of cisplatin in NPC cells. Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1-mediated p27 degradation. Jab1 therefore represents a novel diagnostic marker and therapeutic target in patients with NPC.
authors.affiliation: Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, PR China.
authors.forename: Yunbao
authors.initials: Y
authors.lastname: Pan
authors.forename: Qingxiu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Fan
authors.forename: Huizhong
authors.initials: H
authors.lastname: Zhang
authors.forename: Francois X
authors.initials: FX
authors.lastname: Claret
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000075686:COP9 Signalosome Complex; D002277:Carcinoma; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000209:etiology*; D010447:Peptide Hydrolases / Q000032:analysis / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D061988:Proteasome Inhibitors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin