Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Suppression of Jab1/CSN5 induces radio- and chemo-sensitivity in nasopharyngeal carcinoma through changes to the DNA damage and repair pathways

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus-associated malignancy most common in East Asia and Africa. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin. Increased DNA damage repair is one of the mechanisms contributing to this resistance. Jab1/CSN5 is a multifunctional protein that participates in controlling cell proliferation and the stability of multiple proteins. Jab1 overexpression has been found to correlate with poor prognosis in several tumor types. However, the biological significance of Jab1 activity in response to cancer treatment is unclear. In this study, we used three NPC cell lines (CNE1, CNE2 and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA-damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV) radiation. We found that Jab1 was overexpressed in two relatively cisplatin-, IR- and UV-resistant NPC cell lines, and knocking down its expression conferred sensitivity to cisplatin, IR and UV radiation. By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV radiation. Moreover, we provide a mechanism by which Jab1 positively regulated Rad51 through p53-dependent pathway, and increased ectopic expression of Rad51 conferred cellular resistance to cisplatin, IR and UV radiation in Jab1-deficient cells. Taken together, our findings suggest that Jab1 has an important role in the cellular response to cisplatin and irradiation by regulating DNA damage and repair pathways. Therefore, Jab1 is a novel biomarker for predicting the outcome of patients with NPC who are treated with DNA-damaging agents.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Wei WI, Sham JS. . Nasopharyngeal carcinoma. Lancet 2005; 365: 2041–2054.

    Article  PubMed  Google Scholar 

  2. Lo KW, Chung GT, To KF. . Deciphering the molecular genetic basis of NPC through molecular, cytogenetic, and epigenetic approaches. Semin Cancer Biol 2012; 22: 79–86.

    Article  CAS  PubMed  Google Scholar 

  3. Spano JP, Busson P, Atlan D, Bourhis J, Pignon JP, Esteban C et al Nasopharyngeal carcinomas: an update. Eur J Cancer 2003; 39: 2121–2135.

    Article  PubMed  Google Scholar 

  4. Lo KW, To KF, Huang DP. . Focus on nasopharyngeal carcinoma. Cancer Cell 2004; 5: 423–428.

    Article  CAS  PubMed  Google Scholar 

  5. Hui EP, Ma BB, Leung SF, King AD, Mo F, Kam MK et al Randomized phase II trial of concurrent cisplatin-radiotherapy with or without neoadjuvant docetaxel and cisplatin in advanced nasopharyngeal carcinoma. J Clin Oncol 2009; 27: 242–249.

    Article  CAS  PubMed  Google Scholar 

  6. Le QT, Tate D, Koong A, Gibbs IC, Chang SD, Adler JR et al Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2003; 56: 1046–1054.

    Article  PubMed  Google Scholar 

  7. Yip KW, Mocanu JD, Au PY, Sleep GT, Huang D, Busson P et al Combination bcl-2 antisense and radiation therapy for nasopharyngeal cancer. Clin Cancer Res 2005; 11: 8131–8144.

    Article  CAS  PubMed  Google Scholar 

  8. Liu RY, Dong Z, Liu J, Yin JY, Zhou L, Wu X et al Role of eIF3a in regulating cisplatin sensitivity and in translational control of nucleotide excision repair of nasopharyngeal carcinoma. Oncogene 2011; 30: 4814–4823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Claret FX, Hibi M, Dhut S, Toda T, Karin M. . A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 1996; 383: 453–457.

    Article  CAS  PubMed  Google Scholar 

  10. Shackleford TJ, Claret FX . JAB1/CSN5: a new player in cell cycle control and cancer. Cell Div 2010; 5: 26.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kouvaraki MA, Rassidakis GZ, Tian L, Kumar R, Kittas C, Claret FX. . Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27(Kip1). Cancer Res 2003; 63: 2977–2981.

    CAS  PubMed  Google Scholar 

  12. Rassidakis GZ, Claret FX, Lai R, Zhang Q, Sarris AH, McDonnell TJ et al Expression of p27(Kip1) and c-Jun activation binding protein 1 are inversely correlated in systemic anaplastic large cell lymphoma. Clin Cancer Res 2003; 9: 1121–1128.

    CAS  PubMed  Google Scholar 

  13. Kouvaraki MA, Korapati AL, Rassidakis GZ, Tian L, Zhang Q, Chiao P et al Potential role of Jun activation domain-binding protein 1 as a negative regulator of p27kip1 in pancreatic adenocarcinoma. Cancer Res 2006; 66: 8581–8589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pan Y, Zhang Q, Tian L, Wang X, Fan X, Zhang H et al Jab1/CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma. Cancer Res 2012; 72: 1890–1900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tian L, Peng G, Parant JM, Leventaki V, Drakos E, Zhang Q et al Essential roles of Jab1 in cell survival, spontaneous DNA damage and DNA repair. Oncogene 2010; 29: 6125–6137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ciccia A, Elledge SJ. . The DNA damage response: making it safe to play with knives. Mol Cell 2010; 40: 179–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. . Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 1994; 371: 346–347.

    Article  CAS  PubMed  Google Scholar 

  18. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M et al Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995; 376: 37–43.

    Article  CAS  PubMed  Google Scholar 

  19. Siddik ZH. . Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003; 22: 7265–7279.

    Article  CAS  PubMed  Google Scholar 

  20. Cruet-Hennequart S, Villalan S, Kaczmarczyk A, O'Meara E, Sokol AM, Carty MP. . Characterization of the effects of cisplatin and carboplatin on cell cycle progression and DNA damage response activation in DNA polymerase eta-deficient human cells. Cell Cycle 2009; 8: 3039–3050.

    Article  PubMed  Google Scholar 

  21. Lee JH, Kang Y, Khare V, Jin ZY, Kang MY, Yoon Y et al The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage. Oncogene 2010; 29: 1431–1450.

    Article  CAS  PubMed  Google Scholar 

  22. Pabla N, Ma Z, McIlhatton MA, Fishel R, Dong Z. . hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. J Biol Chem 2011; 286: 10411–10418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pedram A, Razandi M, Evinger AJ, Lee E, Levin ER. . Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair. Mol Biol Cell 2009; 20: 3374–3389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Revet I, Feeney L, Bruguera S, Wilson W, Dong TK, Oh DH et al Functional relevance of the histone gammaH2Ax in the response to DNA damaging agents. Proc Natl Acad Sci USA 2011; 108: 8663–8667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dmitrieva NI, Cui K, Kitchaev DA, Zhao K, Burg MB. . DNA double-strand breaks induced by high NaCl occur predominantly in gene deserts. Proc Natl Acad Sci USA 2011; 108: 20796–20801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Buscemi G, Perego P, Carenini N, Nakanishi M, Chessa L, Chen J et al Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene 2004; 23: 7691–7700.

    Article  CAS  PubMed  Google Scholar 

  27. Shinohara A, Ogawa H, Ogawa T. . Rad51 protein involved in repair and recombination in S. cerevisiae is a RecA-like protein. Cell 1992; 69: 457–470.

    Article  CAS  PubMed  Google Scholar 

  28. Arias-Lopez C, Lazaro-Trueba I, Kerr P, Lord CJ, Dexter T, Iravani M et al p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene. EMBO Rep 2006; 7: 219–224.

    Article  CAS  PubMed  Google Scholar 

  29. Hannay JA, Liu J, Zhu QS, Bolshakov SV, Li L, Pisters PW et al Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation. Mol Cancer Ther 2007; 6: 1650–1660.

    Article  CAS  PubMed  Google Scholar 

  30. Qing Y, Yamazoe M, Hirota K, Dejsuphong D, Sakai W, Yamamoto KN et al The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination. PLoS Genet 2011; 7: e1002148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cheung HW, Jin DY, Ling MT, Wong YC, Wang Q, Tsao SW et al Mitotic arrest deficient 2 expression induces chemosensitization to a DNA-damaging agent, cisplatin, in nasopharyngeal carcinoma cells. Cancer Res 2005; 65: 1450–1458.

    Article  CAS  PubMed  Google Scholar 

  32. Elledge SJ. . Cell cycle checkpoints: preventing an identity crisis. Science 1996; 274: 1664–1672.

    Article  CAS  PubMed  Google Scholar 

  33. Mikhailov A, Cole RW, Rieder CL. . DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint. Curr Biol 2002; 12: 1797–1806.

    Article  CAS  PubMed  Google Scholar 

  34. Ma W, Lin Y, Xuan W, Iversen PL, Smith LJ, Benchimol S. . Inhibition of p53 expression by peptide-conjugated phosphorodiamidate morpholino oligomers sensitizes human cancer cells to chemotherapeutic drugs. Oncogene 2012; 31: 1024–1033.

    Article  CAS  PubMed  Google Scholar 

  35. Feng Z, Xu S, Liu M, Zeng YX, Kang T. . Chk1 inhibitor Go6976 enhances the sensitivity of nasopharyngeal carcinoma cells to radiotherapy and chemotherapy in vitro and in vivo. Cancer Lett 2010; 297: 190–197.

    Article  CAS  PubMed  Google Scholar 

  36. Tsuzuki T, Fujii Y, Sakumi K, Tominaga Y, Nakao K, Sekiguchi M et al Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci USA 1996; 93: 6236–6240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sonoda E, Sasaki MS, Buerstedde JM, Bezzubova O, Shinohara A, Ogawa H et al Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. Embo J 1998; 17: 598–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Raderschall E, Stout K, Freier S, Suckow V, Schweiger S, Haaf T. . Elevated levels of Rad51 recombination protein in tumor cells. Cancer Res 2002; 62: 219–225.

    CAS  PubMed  Google Scholar 

  39. Vispe S, Cazaux C, Lesca C, Defais M. . Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. Nucleic Acids Res 1998; 26: 2859–2864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Collis SJ, Tighe A, Scott SD, Roberts SA, Hendry JH, Margison GP. . Ribozyme minigene-mediated RAD51 down-regulation increases radiosensitivity of human prostate cancer cells. Nucleic Acids Res 2001; 29: 1534–1538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Russell JS, Brady K, Burgan WE, Cerra MA, Oswald KA, Camphausen K et al Gleevec-mediated inhibition of Rad51 expression and enhancement of tumor cell radiosensitivity. Cancer Res 2003; 63: 7377–7383.

    CAS  PubMed  Google Scholar 

  42. Zhang Q, Tian L, Mansouri A, Korapati AL, Johnson TJ, Claret FX. . Inducible expression of a degradation-resistant form of p27Kip1 causes growth arrest and apoptosis in breast cancer cells. FEBS Lett 2005; 579: 3932–3940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mansouri A, Ridgway LD, Korapati AL, Zhang Q, Tian L, Wang Y et al Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells. J Biol Chem 2003; 278: 19245–19256.

    Article  CAS  PubMed  Google Scholar 

  44. Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN et al Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 2009; 15: 7538–7546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Zahid H Siddik, Do Youn Oh for helpful discussions and Ronald Glaser for kindly providing HONE1 cells. This work was supported by a fellowship from the China Scholarship Council (2010638087 to YP) and a grant from the National Cancer Institute (RO1-CA90853 to FXC). The University of Texas MD Anderson Functional Proteomics Core Facility is supported by an NCI Cancer Center Support Grant (CA16672); the National Natural Science Foundation of China (81071837; 30670627); Natural Science Foundation of Guangdong Province, China (9251008901000005; 06021210) and Scientific and Technological Project of Guangdong, China (2008A030201009; 2010B050700016 to HY). We thank Kate J Newberry and Sunita Patterson for editing the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F X Claret.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pan, Y., Zhang, Q., Atsaves, V. et al. Suppression of Jab1/CSN5 induces radio- and chemo-sensitivity in nasopharyngeal carcinoma through changes to the DNA damage and repair pathways. Oncogene 32, 2756–2766 (2013). https://doi.org/10.1038/onc.2012.294

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.294

Keywords

This article is cited by

Search

Quick links