TY - JOUR
T1 - Suppression of Jab1/CSN5 induces radio-and chemo-sensitivity in nasopharyngeal carcinoma through changes to the DNA damage and repair pathways
AU - Pan, Y.
AU - Zhang, Q.
AU - Atsaves, V.
AU - Yang, H.
AU - Claret, F. X.
N1 - Funding Information:
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.
PY - 2013/5/30
Y1 - 2013/5/30
N2 - 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.
AB - 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.
KW - Epstein-Barr virus-associated malignancy
KW - RPPA
KW - cisplatin
KW - ionizing radiation
KW - nasopharyngeal carcinoma
KW - ultraviolet radiation
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U2 - 10.1038/onc.2012.294
DO - 10.1038/onc.2012.294
M3 - Article
C2 - 22797071
AN - SCOPUS:84879420588
SN - 0950-9232
VL - 32
SP - 2756
EP - 2766
JO - Oncogene
JF - Oncogene
IS - 22
ER -