CHAF1B induces radioresistance by promoting DNA damage repair in nasopharyngeal carcinoma
| Autor: | Yunting Jian, Jingjing Miao, Meng Wang, Chong Zhao, Huageng Huang, Lin Wang, Muping Di, Xiangfu Chen, Yue Li, Chuyong Lin, Boyu Chen, Ying Ouyang |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine DNA Repair DNA damage CHAF1B Mice Nude Apoptosis RM1-950 DNA-PK pathway Radiation Tolerance Flow cytometry Mice 03 medical and health sciences 0302 clinical medicine Nude mouse Cell Line Tumor Radioresistance medicine Nasopharyngeal carcinoma Animals Humans DNA damage repair Radiosensitivity Pharmacology Mice Inbred BALB C DNA synthesis biology medicine.diagnostic_test Chemistry Nasopharyngeal Neoplasms General Medicine Middle Aged medicine.disease biology.organism_classification Xenograft Model Antitumor Assays Up-Regulation Gene Expression Regulation Neoplastic Chromatin Assembly Factor-1 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Female Therapeutics. Pharmacology DNA Damage |
| Zdroj: | Biomedicine & Pharmacotherapy, Vol 123, Iss, Pp 109748-(2020) |
| ISSN: | 0753-3322 |
| Popis: | Background Radiotherapy is the main treatment for nasopharyngeal carcinoma (NPC); however radioresistance restricts its efficacy. Therefore, new molecular regulators are required to improve the radiosensitivity of NPC. Chromatin assembly factor 1 subunit B (CHAF1B) plays a role in DNA synthesis and repair, and participates in the progression of various malignancies. However, the expression and function of CHAF1B in NPC is unclear. Methods The expression of CHAF1B was determined using real-time PCR and western blotting. CHAF1B expression in 160 human NPC tissue samples was evaluated using immunochemistry (IHC). The correlations between CHAF1B expression and NPC clinicopathological features were determined. The effect of CHAF1B on the radiosensitivity of NPC cells was detected using 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and colony formation assays. Apoptosis rates were analyzed using flow cytometry. A nude mouse subcutaneous xenograft model and living fluorescence imaging were applied to evaluate tumor regression in vivo. The molecular mechanisms of radioresistance were confirmed by bioinformatics analysis and detection of phosphorylated H2A histone family member X (γH2AX) foci. Results Significantly increased CHAF1B levels were observed in NPC tissues, which correlated positively with radioresistance and poor prognosis. In addition, CHAF1B was upregulated in radioresistant NPC cell lines. Overexpression of CHAF1B reduced, while silencing of CHAF1B enhanced, the radiosensitivity of NPC cells in vitro and in vivo. Mechanistically, CHAF1B inhibited NPC cell apoptosis by promoting DNA damage repair. Finally, the DNA-dependent protein kinase (DNA-PK) pathway was observed to be essential for CHAF1B promotion of DNA damage repair-mediated radioresistance. Conclusion The results suggested CHAF1B enhances radioresistance by promoting DNA damage repair and inhibiting cell apoptosis, in a DNA-PK pathway-dependent manner. CHAF1B may serve as a novel factor for predicting radiorsensitivity. Besides, DNA-dependent protein kinase inhibitor could serve as a radiosensitizer for patients with NPC and high CHAF1B expression. |
| Databáze: | OpenAIRE |
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