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OTU deubiquitinase 4 is silenced and radiosensitizes non-small cell lung cancer cells via inhibiting DNA repair.(Report)

Background Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC). Identifying novel radiosensitizers will greatly increase the efficacy of radiotherapy and benefit more patients. OTU deubiquitinase 4 (OTUD4) has been reported involved in DNA damage repair pathways an... Full description

Journal Title: Cancer Cell International April 15, 2019, Vol.19(1)
Main Author: Wu, Zhiqiang
Other Authors: Qiu, Minghan , Guo, Yu , Zhao, Jinlin , Liu, Zhuang , Wang, Hui , Meng, Maobin , Yuan, Zhiyong , Mi, Zeyun
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: DOI: 10.1186/s12935-019-0816-z
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recordid: gale_ofa583182306
title: OTU deubiquitinase 4 is silenced and radiosensitizes non-small cell lung cancer cells via inhibiting DNA repair.(Report)
format: Article
creator:
  • Wu, Zhiqiang
  • Qiu, Minghan
  • Guo, Yu
  • Zhao, Jinlin
  • Liu, Zhuang
  • Wang, Hui
  • Meng, Maobin
  • Yuan, Zhiyong
  • Mi, Zeyun
subjects:
  • Non-Small Cell Lung Cancer – Genetic Aspects
  • Non-Small Cell Lung Cancer – Drug Therapy
  • Non-Small Cell Lung Cancer – Research
  • DNA Damage – Research
  • DNA Damage – Physiological Aspects
  • Antineoplastic Agents – Research
ispartof: Cancer Cell International, April 15, 2019, Vol.19(1)
description: Background Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC). Identifying novel radiosensitizers will greatly increase the efficacy of radiotherapy and benefit more patients. OTU deubiquitinase 4 (OTUD4) has been reported involved in DNA damage repair pathways and could be a potential target for chemotherapy therapy. This study aimed to investigate the roles of OTUD4 in regulation of radiosensitivity of NSCLC via modulating DNA repair. Methods The expression of OTUD4, [gamma]-H2Ax and ATM/CHK2/p53 pathway-related signaling molecules were detected by Western blotting and QRT-PCR. The methylation of OTUD4 promoter was investigated by 5-aza-deoxycytidine treatment, methylation-specific PCR and bisulfite genomic sequencing assays. Radiosensitivity was assessed by the clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage and repair were determined by comet assay, [gamma]-H2Ax foci staining and flow cytometry. Results OTUD4 is dramatically downregulated in NSCLC and its downregulation significantly correlates with poor prognosis of NSCLC patients. Promoter hypermethylation is responsible for the loss of OTUD4 expression in NSCLC cells. Overexpression of OTUD4 increases radiosensitivity of NSCLC cells exhibiting as impaired clonogenic formation ability, enhanced cell cycle arrest and increased cell apoptosis. Moreover, molecular mechanism study reveals that OTUD4 radiosensitizs NSCLC cells via ATM/CHK2/P53 signaling and inhibiting homology-directed repair of DNA double strand breaks induced by ionizing radiation. Conclusions This study uncovers a tumor-suppressing role of OTUD4 and that OTUD4 is a potential radiosensitizer for NSCLC. Keywords: Non-small cell lung cancer, Radiosensitizer, OTUD4, Homology repair, DNA methylation
language: eng
source:
identifier: DOI: 10.1186/s12935-019-0816-z
fulltext: fulltext
url: Link


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titleOTU deubiquitinase 4 is silenced and radiosensitizes non-small cell lung cancer cells via inhibiting DNA repair.(Report)
creatorWu, Zhiqiang ; Qiu, Minghan ; Guo, Yu ; Zhao, Jinlin ; Liu, Zhuang ; Wang, Hui ; Meng, Maobin ; Yuan, Zhiyong ; Mi, Zeyun
ispartofCancer Cell International, April 15, 2019, Vol.19(1)
identifierDOI: 10.1186/s12935-019-0816-z
subjectNon-Small Cell Lung Cancer – Genetic Aspects ; Non-Small Cell Lung Cancer – Drug Therapy ; Non-Small Cell Lung Cancer – Research ; DNA Damage – Research ; DNA Damage – Physiological Aspects ; Antineoplastic Agents – Research
descriptionBackground Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC). Identifying novel radiosensitizers will greatly increase the efficacy of radiotherapy and benefit more patients. OTU deubiquitinase 4 (OTUD4) has been reported involved in DNA damage repair pathways and could be a potential target for chemotherapy therapy. This study aimed to investigate the roles of OTUD4 in regulation of radiosensitivity of NSCLC via modulating DNA repair. Methods The expression of OTUD4, [gamma]-H2Ax and ATM/CHK2/p53 pathway-related signaling molecules were detected by Western blotting and QRT-PCR. The methylation of OTUD4 promoter was investigated by 5-aza-deoxycytidine treatment, methylation-specific PCR and bisulfite genomic sequencing assays. Radiosensitivity was assessed by the clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage and repair were determined by comet assay, [gamma]-H2Ax foci staining and flow cytometry. Results OTUD4 is dramatically downregulated in NSCLC and its downregulation significantly correlates with poor prognosis of NSCLC patients. Promoter hypermethylation is responsible for the loss of OTUD4 expression in NSCLC cells. Overexpression of OTUD4 increases radiosensitivity of NSCLC cells exhibiting as impaired clonogenic formation ability, enhanced cell cycle arrest and increased cell apoptosis. Moreover, molecular mechanism study reveals that OTUD4 radiosensitizs NSCLC cells via ATM/CHK2/P53 signaling and inhibiting homology-directed repair of DNA double strand breaks induced by ionizing radiation. Conclusions This study uncovers a tumor-suppressing role of OTUD4 and that OTUD4 is a potential radiosensitizer for NSCLC. Keywords: Non-small cell lung cancer, Radiosensitizer, OTUD4, Homology repair, DNA methylation
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titleOTU deubiquitinase 4 is silenced and radiosensitizes non-small cell lung cancer cells via inhibiting DNA repair.(Report)
descriptionBackground Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC). Identifying novel radiosensitizers will greatly increase the efficacy of radiotherapy and benefit more patients. OTU deubiquitinase 4 (OTUD4) has been reported involved in DNA damage repair pathways and could be a potential target for chemotherapy therapy. This study aimed to investigate the roles of OTUD4 in regulation of radiosensitivity of NSCLC via modulating DNA repair. Methods The expression of OTUD4, [gamma]-H2Ax and ATM/CHK2/p53 pathway-related signaling molecules were detected by Western blotting and QRT-PCR. The methylation of OTUD4 promoter was investigated by 5-aza-deoxycytidine treatment, methylation-specific PCR and bisulfite genomic sequencing assays. Radiosensitivity was assessed by the clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage and repair were determined by comet assay, [gamma]-H2Ax foci staining and flow cytometry. Results OTUD4 is dramatically downregulated in NSCLC and its downregulation significantly correlates with poor prognosis of NSCLC patients. Promoter hypermethylation is responsible for the loss of OTUD4 expression in NSCLC cells. Overexpression of OTUD4 increases radiosensitivity of NSCLC cells exhibiting as impaired clonogenic formation ability, enhanced cell cycle arrest and increased cell apoptosis. Moreover, molecular mechanism study reveals that OTUD4 radiosensitizs NSCLC cells via ATM/CHK2/P53 signaling and inhibiting homology-directed repair of DNA double strand breaks induced by ionizing radiation. Conclusions This study uncovers a tumor-suppressing role of OTUD4 and that OTUD4 is a potential radiosensitizer for NSCLC. Keywords: Non-small cell lung cancer, Radiosensitizer, OTUD4, Homology repair, DNA methylation
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abstractBackground Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC). Identifying novel radiosensitizers will greatly increase the efficacy of radiotherapy and benefit more patients. OTU deubiquitinase 4 (OTUD4) has been reported involved in DNA damage repair pathways and could be a potential target for chemotherapy therapy. This study aimed to investigate the roles of OTUD4 in regulation of radiosensitivity of NSCLC via modulating DNA repair. Methods The expression of OTUD4, [gamma]-H2Ax and ATM/CHK2/p53 pathway-related signaling molecules were detected by Western blotting and QRT-PCR. The methylation of OTUD4 promoter was investigated by 5-aza-deoxycytidine treatment, methylation-specific PCR and bisulfite genomic sequencing assays. Radiosensitivity was assessed by the clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage and repair were determined by comet assay, [gamma]-H2Ax foci staining and flow cytometry. Results OTUD4 is dramatically downregulated in NSCLC and its downregulation significantly correlates with poor prognosis of NSCLC patients. Promoter hypermethylation is responsible for the loss of OTUD4 expression in NSCLC cells. Overexpression of OTUD4 increases radiosensitivity of NSCLC cells exhibiting as impaired clonogenic formation ability, enhanced cell cycle arrest and increased cell apoptosis. Moreover, molecular mechanism study reveals that OTUD4 radiosensitizs NSCLC cells via ATM/CHK2/P53 signaling and inhibiting homology-directed repair of DNA double strand breaks induced by ionizing radiation. Conclusions This study uncovers a tumor-suppressing role of OTUD4 and that OTUD4 is a potential radiosensitizer for NSCLC. Keywords: Non-small cell lung cancer, Radiosensitizer, OTUD4, Homology repair, DNA methylation
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