Suppression of Jab1/CSN5 induces radio- and chemo-sensitivity in nasopharyngeal carcinoma through changes to the DNA damage and repair pathways.
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.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Pan
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Zhang
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Atsaves
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Yang
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Claret
D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D000075686:COP9 Signalosome Complex; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D002945:Cisplatin