Abstract
BackgroundRadiotherapy 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.MethodsThe expression of OTUD4, γ-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, γ-H2Ax foci staining and flow cytometry.ResultsOTUD4 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.ConclusionsThis study uncovers a tumor-suppressing role of OTUD4 and that OTUD4 is a potential radiosensitizer for NSCLC.
Highlights
Radiotherapy is becoming one major therapeutics for non-small cell lung cancer (NSCLC)
OTU deubiquitinase 4 (OTUD4) is downregulated in lung cancer and its downregulation associated with poor prognosis of patients with lung cancer First, the expression of OTUD4 in non-small cell lung cancer was analyzed
Analysis of TCGA dataset showed that OTUD4 level was significantly depressed in both lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) tissues compared with normal lung tissues (Fig. 1e)
Summary
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. This study aimed to investigate the roles of OTUD4 in regulation of radiosensitivity of NSCLC via modulating DNA repair. Non-small cell lung cancer (NSCLC) is the main histological type of lung cancer, which accounts for nearly 85% of all cases of lung cancer [2]. Radiotherapy is becoming more and more important for treatment of NSCLC. Radiotherapy, especially stereotactic body radiotherapy (SBRT), achieved promising benefit for NSCLC patients [3]. Radioresistance hinders further improving efficacy of radiotherapy and results in treatment failure in patients. Elucidating the mechanism of radioresistance and finding/developing effective radiosensitizer are very important
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