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. Author manuscript; available in PMC: 2013 Dec 30.
Published in final edited form as: Cancer Lett. 2012 Aug 4;326(2):155–160. doi: 10.1016/j.canlet.2012.07.033

Targeting Jab1/CSN5 in nasopharyngeal carcinoma

Yunbao Pan 1,2, François X Claret 1,3
PMCID: PMC3474602  NIHMSID: NIHMS398850  PMID: 22867945

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus–associated head and neck cancer that is most common in eastern Asia. Epstein-Barr virus infection, environmental factors, and genetic susceptibility play important roles in NPC pathogenesis. Jab1/CSN5 is a multifunctional protein that participates in affecting integrin signaling, controlling cell proliferation and apoptosis, and regulating genomic instability and DNA repair. Correlation of Jab1/CSN5 overexpression with poor prognosis for NPC provides evidence that it is involved in the tumorigenic process. In this review, we highlight recent advances in studies of the oncogenic role of Jab1/CSN5 in NPC and its potential as a therapeutic target for this cancer.

Keywords: nasopharyngeal carcinoma, tumorigenesis, Epstein-Barr virus-associated malignancy, p27Kip1, Jab1/CSN5, DNA repair

1. Introduction

Nasopharyngeal carcinoma (NPC) is a head and neck cancer with remarkable ethnic and geographic distribution [1, 2]. This Epstein-Barr virus (EBV)-associated epithelial malignancy is relatively rare in most parts of the world but is a significant disease burden in Southern China, Southeast Asia, Northern Africa, and Alaskan Inuits with an annual incidence of about 20 per 100,000 people in endemic areas [2, 3]. The incidence of NPC is also high in some areas of northern Africa [1]. Each year, 80,000 new cases of NPC are diagnosed worldwide, and 50,000 individuals die of this disease [3]. The World Health Organization classifies NPC on the basis of histology [4]: type 1 NPC (keratinizing squamous carcinoma) is characterized by well-differentiated cells that produce keratin; type 2 NPC (nonkeratinizing squamous carcinoma) varies in cell differentiation but does not produce keratin; and type 3 NPC, which is also nonkeratinizing but less differentiated, has highly variable cell types (clear, spindle, and anaplastic cells).

Nonkeratinizing carcinoma is the major subtype of NPC, accounting for up to 99% of all cases in endemic regions. Although NPC is characterized by a strong association with EBV infection and intensive infiltration of lymphocytes, EBV infection, is generally absent from type 1 NPC cases, especially in non-endemic areas [5]. However, more recent data indicate that almost all NPC patients, regardless of their tumors’ histologic subtype, have comorbid EBV infections, which is strong evidence for EBV as the etiology for NPC [4, 6]. This close association with EBV makes NPC unique from other head and neck cancers. Although latent EBV infection may contribute to the initiation of NPC, increasing evidence supports that persistent EBV infection in nasopharyngeal epithelial cells is dependent on specific existing genetic changes [7, 8]. However, EBV infection alone is not sufficient to transform nasopharyngeal epithelial cells. Accumulation of additional genetic and epigenetic abnormalities is necessary to drive the tumorigenic process [9].

Although radiotherapy and chemotherapy have improved NPC survival rates [10], the prognosis for metastatic NPC remains poor, even with combined radiotherapy and chemotherapy, with relapse rates as high as 82% [11]. Unfortunately, the majority of NPC cases are diagnosed at an advanced stage because of nonspecific presenting symptoms, delay in seeking treatment after the onset of symptoms, and the difficulty of performing a thorough nasopharyngeal examination. In light of this, more targeted treatments of NPC must be developed, and the molecular changes leading to NPC tumorigenesis must be clarified.

Emerging evidence has demonstrated that the oncoprotein Jab1/constitutive photomorphogenic 9 signalosome subunit 5 (CSN5) is critically involved in the pathogenesis of NPC [12, 13]. Therefore, in this review, we provide an overview of the role of Jab1/CSN5 in NPC tumorigenesis and summarize recently findings that highlight the novel roles of Jab1/CSN5 in this process. Furthermore, we summarize approaches to inhibition of Jab1/CSN5 expression and suggest that Jab1/CSN5 is a promising therapeutic target in combating human NPC.

2. Jab1/CSN5 is an integral component of the CSN complex

When the CSN complex was first identified in plants, it was shown to be an essential regulator of light-mediated development [14, 15]. The CSN complex is about 450 kDa in mass and comprises eight core subunits—CSN1–CSN8—in order of descending size. These subunits are highly conserved across diverse species. The CSN complex is essential for both plant and animal development [16].

Our group originally identified Jab1/CSN5 as a c-Jun coactivator, and other groups subsequently discovered it to be the fifth member and an integral component of the CSN complex [17, 18]. Of the eight CSN subunits, CSN5 is unique in that it not only harbors the catalytic center of CSN isopeptidase activity but also stably exists independently of the CSN complex in vivo [18]. Jab1/CSN5 actively participates in important biologic functions, both as part of the CSN holocomplex and independently of the CSN. A large fraction of Jab1/CSN5 is found in the free form [19]. Whereas the CSN-associated Jab1/CSN5 is mostly nuclear, the free forms appear to be both cytoplasmic and nuclear [6, 19, 20]. The dependence of CSN5 nuclear accumulation on other subunits has been clearly demonstrated in the budding yeast CSN-like complex [21]. Although our studies indicated that ectopic Jab1 has important biologic functions in NPC and that Jab1 appears to be both cytoplasmic and nuclear. Whether Jab1 acts as a complex or independently of a complex in NPC remains to be identified.

3. Jab1/CSN5 is a proto-oncoprotein

Jab1/CSN5 is involved in cell-cycle progression through degradation of several essential targets [22]. For example, studies have demonstrated that Jab1/CSN5 is essential for p27 degradation, thereby limiting cells in G1 phase prior to entry into S phase [12, 19, 23, 24]. That finding raised the question of whether the observed lower levels of p27 in human cancers, which are lower than those in normal tissue, are caused by overexpression of Jab1/CSN5. Indeed, accumulating evidence has shown that Jab1/CSN5 expression is inversely correlated with p27 and poor survival in various human malignancies [22]. Researchers have identified specific substrates of Jab1/CSN5 in addition to the cell cycle inhibitor p27, including the tumor suppressor proteins p53 [25], cyclin E [26], Smad 4/7 [27, 28], LHR [29], and others [22]. These substrates of Jab1/CSN5 are involved in many cellular processes, such as cell-cycle regulation, proliferation, apoptosis, angiogenesis, and survival. Without a doubt, Jab1/CSN5 has important functions in the regulation of these cellular processes owing to degradation of these tumor suppressors [17, 30]. Because Jab1/CSN5 is responsible for degradation of the tumor suppressor proteins listed above and for promoting the transcription of oncogenes, it is believed to function as an oncoprotein.

Many studies have demonstrated that Jab1/CSN5 is overexpressed in a variety of human cancers, including pituitary cancer [31], pancreatic cancer [23, 32], breast carcinoma [33, 34], lung cancer [35, 36], NPC [12], and many others [22]. Moreover, investigators have found that Jab1/CSN5 is a prognostic marker for multiple cancers. For example, overexpression of Jab1/CSN5 is associated with lymph node metastasis of laryngeal squamous cell carcinoma [37] and hepatocellular carcinoma [38], leading to poor survival in patients with these cancers. Similarly, Jab1/CSN5 expression is correlated with tumor size in thyroid carcinoma cases [39]. Additionally, elevated Jab1/CSN5 expression is related to metastasis of hepatocellular carcinoma [38] and oral squamous cell carcinoma [40]. Jab1/CSN5 expression is considered a biomarker of poor prognosis for many cancers, including NPC [12]. Interestingly, our recent findings showed that Jab1/CSN5 mediates resistance of NPC cell lines to apoptosis induced by cisplatin, ultraviolet (UV) radiation, and ionizing radiation (IR) [12]. Jab1/CSN5 is therefore believed to be a proto-oncoprotein.

4. The role of Jab1/CSN5 in progression of NPC

A growing body of evidence strongly suggests that Jab1/CSN5 plays critical roles in head and neck tumorigenesis. For example, authors have reported Jab1/CSN5 to be overexpressed in thyroid carcinoma cells with low levels of p27 expression [39]. Emerging evidence has also revealed that Jab1/CSN5 plays important roles in cell growth, apoptotic cell death, and metastasis in human head and neck cancer cases [12, 41]. However, the molecular mechanism or mechanisms by which Jab1/CSN5 facilitates NPC progression remain largely elusive. Herein we describe some recent advances in understanding the role of Jab1/CSN5 in NPC progression. Specifically, in the following sections, we summarize the results of emerging studies of Jab1/CSN5 as well as its therapeutic implications for NPC.

5. Jab1/CSN5 is overexpressed in NPC

Researchers have widely accepted that Jab1/CSN5 is frequently overexpressed in a variety of human cancers, including NPC. Our group examined Jab1/CSN5 and p27 protein expression in NPC specimens and its association with clinical outcome [12]. Our immunohistochemical analyses detected Jab1/CSN5 in 30 nasopharyngitis and 45 NPC specimens and showed that Jab1/CSN5 expression was localized to the cytoplasm and nuclei of NPC cells: 74% had cytoplasmic staining and 56% had nuclear staining for Jab1/CSN5. The NPC-staining percentages in these cases were higher than those in noncancerous inflamed nasopharyngeal tissue, which were 10% in the cytoplasm and 16% in the nuclei. In contrast, the nuclear p27 staining percentage was higher in noncancerous inflamed nasopharyngeal tissue (67%) than in NPCs (58%). However, we observed cytoplasmic staining for p27 in 64% of the NPC cases, which was higher than that in noncancerous tissue (37%). Moreover, we observed higher Jab1/CSN5 protein expression in NPC cells than in normal keratinocytes. Furthermore, cytoplasmic Jab1/CSN5 expression in NPCs was inversely associated with nuclear p27 expression and directly correlated with cytoplasmic p27 expression. Our finding of an inverse correlation between Jab1/CSN5 and p27 expression in NPC agrees with our previously published results on breast cancer [33] and pancreatic carcinoma [23], and other groups have reported similar associations in epithelial and lymphoid malignancies [42, 43]. This suggests that Jab1/CSN5 overexpression has a physiologic role in controlling p27 expression in NPC cells.

Although no published findings have explained the reason for the overexpression of Jab1/CSN5 in NPC, we propose two major mechanisms that lead to Jab1/CSN5 aberrant expression in NPC. First, we assessed two databases (cBio and ONCOMINE) and found that Jab1 expression was amplified at chromosome 8Q13.2 in head and neck squamous cell carcinoma. As one kind of head and neck cancer, NPC could have the same Jab1 gene amplification. Second, our recent studies showed that Jab1/CSN5 is transcriptionally activated by the Stat3 signaling pathway in breast cancer [44], and in a similar case, our unpublished data seem to indicate that Stat3 positively regulates Jab1/CSN5 in NPC. Stat3 activation has been found in many human cancers, including NPC, which may result in overexpression of Jab1/CSN5 in NPC. Stat3 activation has been found in many human cancers including NPC, which may result in overexpression of Jab1/CSN5 in NPC. Previous studies [45], showed that the EBV gene LMP1 could activate Stat3, which may result in the overexpression of Jab1/CSN5 in NPC.

6. Jab1/CSN5 predicts poor prognosis for NPC

A number of studies have implicated Jab1/CSN5 in the pathogenesis of several tumor types, and in many cases, specifically correlated it with reduced levels of p27 and poor prognosis [22]. Furthermore, when Jab1/CSN5 and p27 were combined, Jab1+/p27− patients had poorer overall survival, and Jab1+ patients with lymph node metastasis had poorer disease-free and overall survival than did patients with epithelial ovarian tumors [43] and esophageal [46] or laryngeal [47] squamous cell carcinoma. Consistent with these findings, our studies of NPC showed that high expression of Jab1/CSN5 correlated with poor prognosis. We also obtained similar results for patients with nonkeratinizing and keratinizing squamous cell carcinoma [12]. We observed that the median survival durations in patients with negative and weakly positive Jab1/CSN5 tumors were longer than those in patients with highly positive Jab1/CSN5 tumors. Meanwhile, cytoplasmic p27 levels correlated with poor prognosis, and the median survival durations were 19 months in the positive group but 36 months in the negative group [12]. Taken together, these results show that Jab1/CSN5 could be a promising prognostic marker for NPC.

7. Jab1/CSN5 promotes NPC cell growth

Emerging evidence shows that Jab1/CSN5 promotes the growth of cancer cells, including NPC cells. For example, knockdown of Jab1/CSN5 expression by small interfering RNA (siRNA) preferentially inhibited the proliferation of HER-2/neu–overexpressing breast cancer cells [48]. Jab1/CSN5 knockdown also impaired proliferation and enhanced apoptosis in these cells regardless of the genotype of the tumor suppressor p53 [48]. Furthermore, Jab1/CSN5-deficient mice had an embryonically lethal phenotype, suggesting that Jab1/CSN5 is critical for development and survival. Our previous studies showed that Jab1/CSN5-null embryos were smaller than the WT embryos and displayed growth retardation [49]. Jab1/CSN5-null embryos are viable up through the blastocyst stage but begin to exhibit disrupted development at embryonic day 6 and are no longer viable at embryonic day 8.5, which is before gastrulation [49, 50]. Investigators found that several targets of Jab1/CSN5, including p27, p53, c-myc, and cyclin E, were highly expressed in Jab1/CSN5−/− embryos, resulting in impaired proliferation and accelerated apoptosis [49, 50]. Consistent with the role of Jab1/CSN5 in cell growth, treatment with Jab1/CSN5 antisense inhibited the growth of head and neck cancer cells [41]. More recently, our group demonstrated that loss of Jab1/CSN5 resulted in remarkable decreases in the proliferation and adhesion-independent growth of both keratinizing (CNE1) and nonkeratinizing (CNE2 and HONE1) carcinoma cells [12].

8. Jab1/CSN5 regulates cell cycle progression in NPC cells

The cell cycle is tightly controlled by multiple regulatory mechanisms to ensure ordered and coordinated cell-cycle progression. Degradation of key regulators governing cell-cycle progression by the ubiquitin-proteasome system is known to be a major mechanism that ensures orchestration of the cell cycle [51, 52]. Jab1/CSN5 is considered to be a major driving force controlling proper cell-cycle progression via ubiquitination of G1 cyclins and cyclin-dependent kinase inhibitors [22]. For example, p27 is a critical component of the cell-cycle machinery [24]. As an inhibitor of cyclin E-Cdk2, p27 plays a pivotal role in controlling cell proliferation and therefore the cells’ exit from G1 phase and entry into S phase during development and tumorigenesis. Shuttling of p27 from the nucleus to the cytoplasm by Jab1/CSN5 plays an important role in the regulation and function of p27 [19]. Also, authors reported that decreased Jab1/CSN5 expression increased cyclin E stability and that increased Jab1/CSN5 expression stimulated rapid cyclin E degradation [53]. Expression of many cell-cycle regulators, such as cyclins D1, A, and E; Cdk2; Cdc2; p16; p21; c-myc; Bcl-XL; and Geminin, was upregulated in Jab1/CSN5-depleted cells [54, 55]. Therefore, Jab1/CSN5 is correlated with dysregulation of the cell cycle in human cancer cells. In addition, we recently found that Jab1/CSN5 promotes p27-degradation via proteolysis. In contrast, knockdown of endogenous Jab1/CSN5 expression by siRNA in NPC cell lines led to a significant increase in total p27 levels, nuclear accumulation of p27 and the p27/cyclin E/Cdk2 complex, substantial decreases in the number of cells in S phase, and increases in the number of cells in G1 phase [12]. In addition, we confirmed the presence of a direct p27-Jab1/CSN5 interaction in NPC cells. Taken together, these results provide evidence that Jab1/CSN5 negatively controls p27 expression by accelerating p27 degradation and thus regulates cell-cycle progression in NPC cells.

9. Jab1/CSN5 inhibits cisplatin- and radiation- induced apoptosis of NPC cells

Inhibition of NPC cell growth by downregulation of Jab1/CSN5 expression raised the question of whether the inhibition is caused by an increase in apoptosis. Multiple studies have addressed this question. One of them found that Jab1/CSN5 deletion leads to aberrant expression of the apoptosis-triggering protein Fas ligand in pro-B cells [56]. A more recent study showed that by interacting with Jab1/CSN5, Fank1 could suppress apoptosis by activating the AP-1– induced anti-apoptotic pathway [57]. Moreover, we generated mice that were deficient in Jab1/CSN5 and analyzed null embryos and heterozygous Jab1+/− cells. This deficiency in Jab1/CSN5 resulted in early embryonic lethality owing to accelerated apoptosis. Loss of Jab1/CSN5 expression sensitized both primary embryonic fibroblasts and osteosarcoma cells to γ-radiation–induced apoptosis [49]. In contrast, BclGs (Bcl-Gonad short form), a proapoptotic BH3-only protein, and Jab1/CSN5 coexpression synergistically induced apoptosis. Jab1/CSN5 could compete with Bcl-XL/Bcl-2 to bind to BclGs, thus promoting the apoptosis. Recent findings suggest that RNA interference-mediated knockdown of Jab1/CSN5 expression resulted in reduced proapoptotic activity of BclGs in HeLa cells [58], and Lu and colleagues found that several apoptotic and mitotic E2F target genes are poorly expressed in cells lacking Jab1/CSN5 [59]. Interestingly, our studies showed that inhibition of Jab1/CSN5 expression by siRNA for 48 h was insufficient to induce apoptosis in NPC cells [12]. However, we next examined whether knocking down Jab1/CSN5 expression in NPC cells increased UV radiation-, IR-, and cisplatin-induced apoptosis. NPC cells transfected with Jab1/CSN5 siRNA had significantly higher rates of apoptosis after UV irradiation and IR than did cells transfected with control siRNA. We observed similar results with treatment of NPC cells with cisplatin. In contrast, overexpression of Jab1/CSN5 in CNE1 cells blocked UV irradiation- and cisplatin-induced apoptosis [13]. Taken together, these results indicate that Jab1/CSN5 may inhibit irradiation- and cisplatin-induced apoptosis in NPC cells. However, more thorough studies are required to fully understand the underlying molecular and signaling events by which Jab1/CSN5 influences apoptosis in NPC cells.

10. Jab1/CSN5 is involved in NPC resistance to radiotherapy and chemotherapy

Radiotherapy and chemotherapy are the most important treatments of human cancers, including NPC. However, they often fail to cure cancer because resistance to them develops [60]. Thus, increasing drug and radiation sensitivity may offer improved treatment of human cancer [61]. Because radiotherapy and cisplatin-based chemotherapy are the main treatments for solid tumors, Jab1/CSN5 overexpression conceivably contributes to reduce the antitumor effects of these therapies. Indeed, our previous studies in mice indicated that Jab1/CSN5 is essential for DNA repair and is linked with the maintenance of genome integrity and cell survival [49]. Loss of Jab1/CSN5 sensitized cells to γ-radiation–induced apoptosis and increased spontaneous DNA damage and homologous recombination defects [49].

Recently, we analyzed the effects of Jab1/CSN5 on the response of three NPC cell lines to treatment with cisplatin, IR, and UV. We demonstrated that knocking down Jab1/CSN5 expression in these cells sensitized them to all three forms of treatment. Conversely, overexpression of Jab1/CSN5 contributed to cisplatin and radiation resistance in NPC cells by positively regulating the levels of expression of the DNA repair gene Rad51. These observations suggested that Jab1/CSN5 is a major contributor to the resistance of NPC to UV radiation, IR, and cisplatin. Jab1/CSN5 therefore is a novel therapeutic target in patients with NPC and a biomarker for predicting outcomes of cisplatin- and irradiation-based therapy in these patients.

11. Jab1/CSN5 is involved in DNA damage and repair in NPC cells

In mammalian cells, two conserved pathways are involved in double-strand break (DSB) repair: the homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways [62, 63]. We found a decreased level in the Rad51 protein, a key protein in the HR repair pathway [64], in Jab1/CSN5 siRNA-treated U2OS cells. In comparison, the levels of expression of Ku70, known to be an important protein in the NHEJ DNA-repair pathway, and of phospho-Chk2, a key molecule in the transduction of DNA damage signaling induced by DSBs [65, 66], were increased after IR exposure regardless of whether the cells were treated with Jab1/CSN5 or control siRNA. Consistent with these findings, our NPC studies showed that Jab1/CSN5 siRNA-treated HONE1 cells exhibited increased levels of γ-H2AX, which is an early indicator of the presence of DNA DSBs [67]. γ-H2AX spans megabases of DNA flanking a DNA damage site and allows for the recruitment of DNA damage repair proteins. Similarly, the levels of phospho- Chk2, a key molecule in the transduction of DNA damage signals [66], increased in NPC cells after DNA damage exposure regardless of whether the cells were treated with Jab1/CSN5 siRNA (although the phospho-Chk2 levels were higher in Jab1/CSN5-deficient cells). In contrast, Rad51 decreased in Jab1/CSN5 siRNA-treated NPC cells 48 h after treatment with cisplatin or UV radiation. Additionally, we found that γ-H2AX levels were higher but Rad51 levels were lower in Jab1/CSN5 siRNA-treated cells than in control siRNA-treated cells upon IR exposure [13]. These results indicated that Jab1/CSN5 deficiency enhances DNA damage and decreases DNA repair in NPC cells after exposure to DNA-damaging stimuli.

Our recent studies also demonstrated that the protein and mRNA levels of Rad51 were lower in Jab1/CSN5 siRNA and shRNA–treated NPC cells than in control siRNA and shRNA–treated cells. However, after knocking down p53 expression, there was no or less reduction in the Rad51 levels in the Jab1/CSN5 siRNA and shRNA–treated NPC cells. These results indicate that reduction of Rad51 levels in Jab1/CSN5-deficient cells is at least partly p53-dependent [13]. Jab1/CSN5 knockdown not only decreased the level of Rad51 but also affected its activity. Further analysis of DNA repair recovery showed that ectopic expression of Rad51 rescued the defective repair function in NPC cells with knockdown of Jab1/CSN5 expression. These results suggest that depletion of Jab1/CSN5 reduces the expression of Rad51, leading to reduce ability of NPC cells to repair DNA lesions.

12. Conclusions and overall perspective

In this short review article, we provide succinct information on the state of our knowledge of the role of Jab1/CSN5 in NPC (Figure 1). Worth mentioning is that the critical roles of Jab1/CSN5 as an oncoprotein in human cancer progression are largely undetermined, although studies establishing the relationship between Jab1/CSN5 and cancer have emerged in recent years, and several groups have found that multiple signaling pathways, including HER2/Akt [48], interleukin-6/signal transducer and activator of transcription 3 (IL-6/Stat3) [44], epidermal growth factor receptor (EGFR) [68], and migration inhibitory factor MIF [69, 70], can regulate Jab1/CSN5 expression (Figure 2). Jab1/CSN5 is a novel target for the prevention and/or treatment of human cancers, including but not limited to NPC. In conclusion, targeted inactivation of Jab1/CSN5 is likely to become a novel strategy for the prevention of progression of tumors and/or successful treatment of human malignancies, including NPC, in the future.

Figure 1. Overview of the Jab1/CSN5 molecular mechanisms involved in NPC.

Figure 1

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Jab1/CSN5 negatively regulates p27 cell cycle inhibitor levels through protein degradation, resulting in cell cycle dysregulation and enhanced cell proliferation. Jab1/CSN5 also regulates p53 and Rad51, leading to DNA damage repair and apoptosis inhibition in NPC.

Figure 2. Diagram of Jab1/CSN5 cross-talk with other major signaling pathways in cancer.

Figure 2

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IL-6/STAT3, EGFR/ERK, PI3K/AKT, and HER2/Ras regulate the expression of Jab1/CSN5 in cancer.

Acknowledgments

The authors thank Lei An for providing helpful comments on the article. Research in the laboratory of FXC is supported by funds from the National Institutes of Health (1R01CA90853) and Cancer Prevention Research Institute of Texas (RP120451–01). YP is supported by a fellowship from the China Scholarship Council (2010638087). We thank Donald R Norwood and Tamata K. Locke for editing the manuscript.

Footnotes

Conflict of interest statement: The authors have no conflicts of interest to declare.

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