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 NPC patients. 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.

Emerging roles of Jab1/CSN5 in DNA damage response, DNA repair, and cancer

“…Loss of Jab1/CSN5 expression sensitized both primary embryonic fibroblasts and osteosarcoma cells to γ-radiation-induced apoptosis. 5 It is interesting to note that our NPC studies showed that inhibition of Jab1/CSN5 expression with 5 nM of siRNA for 48 h was insufficient to induce apoptosis, 7 whereas higher doses of Jab1/CSN5 siRNA (10 or 20 nM) induced apoptosis (unpublished data), and knocking down Jab1/CSN5 expression in NPC cells increased UV radiation-, ionizing radiation-, and cisplatin-induced apoptosis. 4 In contrast, overexpression of Jab1/CSN5 in CNE1 NPC cells blocked UV radiation-and cisplatin-induced apoptosis.…”

“…For example, knockdown of Jab1/CSN5 inhibited proliferation and induced apoptosis in breast cancer cells 82 and, in our research, NPC cells. 7 Furthermore, Jab1/CSN5-deficient mice were found to have an embryonically lethal phenotype, suggesting that Jab1/CSN5 is critical for fetal development and survival. 5 Our previous studies showed that Jab1/CSN5-null embryos were smaller than wildtype embryos and displayed growth retardation.…”

“…[4][5][6] Furthermore, Jab1/CSN5 is essential for tumor survival and is involved in chemotherapy and radiotherapy resistance. 4,7 In this review, we assess the role of Jab1/CSN5 in DDR and summarize recent findings that highlight the novel roles of Jab1/CSN5 in this process. We also summarize the effect of Jab1/CSN5 inhibition on cancer progression and suggest that inhibition of Jab1/CSN5 is a promising targeted approach to treat human cancer.…”

“…Indeed, accumulating evidence has shown that Jab1/CSN5 overexpression is inversely correlated with p27 expression and with poor survival in various human malignancies. 57 Actually, Jab1/CSN5 is overexpressed in a variety of human cancers, such as ovarian cancer, 58 hepatocellular carcinoma, 59 lung cancer, 60 pancreatic cancer, 61 breast carcinoma, 62 nasopharyngeal carcinoma (NPC), 7 and many others. 57 Moreover, investigators have found that Jab1/CSN5 is a prognostic marker for multiple cancers.…”

A new curcumin analogue exhibits enhanced antitumor activity in nasopharyngeal carcinoma

“…The MTT assay was used to evaluate cell viability as previously described (17). Briefly, NPC cells were seeded in 96-well plates (2,000 cells/well) in RPMI-1640 medium with 10% FBS.…”