抗辐射性
医学
DNA损伤
肺癌
DNA修复
癌症研究
彗星试验
癌症
细胞生物学
病理
DNA
细胞培养
生物化学
遗传学
生物
作者
Juanjuan Wang,Yuting Liu,Di Wu,Chen Tian,Jiaqi Gao,Qifan Yang,Xiaohua Hong,Fei Gu,Kai Zhang,Yue Hu,Shuangbing Xu,Li Liu,Yulan Zeng
标识
DOI:10.1016/j.ijrobp.2024.01.202
摘要
Purpose Radioresistance of lung cancer poses a significant challenge when it comes to the treatment of advanced, recurrent, and metastatic cases. OTUB1, known as Ovarian tumor domain ubiquitin aldehyde binding 1, is a key member of the deubiquitinase OTU superfamily. This protein is involved in various cellular functions, including cell proliferation, iron death, lipid metabolism and cytokine secretion, as well as immune response processes. However, its specific role and molecular mechanism in lung cancer radioresistance remain to be clarified. Methods and Materials The expression levels of OTUB1 in paired lung cancer tissues were determined by immunohistochemistry (IHC). In vitro and in vivo experiments were conducted to investigate the impact of OTUB1 on the growth and proliferation of lung cancer. Coimmunoprecipitation and Western blotting techniques were performed to examine the interaction between OTUB1 and CHK1. The DNA damage response was measured by comet tailing and immunofluorescence staining. KEGG pathways and GO terms were analyzed based on RNA-seq. Results Our findings reveal a high frequency of OTUB1 overexpression, which is associated with an unfavorable prognosis in patients diagnosed with lung cancer. Through comprehensive investigations, we demonstrate that OTUB1 depletion impairs the process of DNA damage repair and overcomes radioresistance. In terms of the underlying mechanism, our study uncovers that OTUB1 deubiquitinates and stabilizes CHK1, which enhances CHK1 stability, thereby regulating DNA damage and repair. Additionally, we identify CHK1 as the primary downstream effector responsible for mediating the functional effects exerted by OTUB1 specifically in lung cancer. Importantly, OTUB1 has the potential to be a valuable marker for improving the efficacy of radiotherapy for lung adenocarcinoma. Conclusions These findings unveil a novel role for OTUB1 in enhancing radioresistance by deubiquitination and stabilizing the expression of CHK1 in lung cancer and indicate that targeting OTUB1 holds great potential as an effective therapeutic approach for enhancing the efficacy of radiotherapy in lung cancer.
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