USP14 Regulates DNA Damage Response and Is a Target for Radiosensitization in Non-Small Cell Lung Cancer.
USP14 Regulates DNA Damage Response and Is a Target for Radiosensitization in Non-Small Cell Lung Cancer.
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DOI：
10.3390/ijms21176383
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发表时间：
2020-09-02
影响因子：
5.6
通讯作者：
Almasan A
中科院分区：
文献类型：
--
作者：
Sharma A;Almasan A
非小细胞肺癌（NSCLC）占肺癌病例的约85%。尽管最近NSCLC治疗取得了进展，但5年生存率仍在23%左右。放疗适用于治疗早期和晚期NSCLC;然而，患者的治疗反应是异质性的。因此，有必要确定新的和更有效的治疗组合。我们已经确定了泛素特异性蛋白酶14（USP 14）是一个调节器的主要双链断裂（DSB）修复途径，在电离辐射（IR）的影响，非同源末端连接（NHEJ）和同源重组（HR）在NSCLC。USP 14是一种蛋白酶体去泛素化酶。IR处理增加了NSCLC细胞系中USP 14的水平和DSB募集。通过克隆形成存活试验测定，使用shUSP 14表达进行基因敲除或使用IU 1进行USP 14药理学抑制可增加NSCLC细胞系的放射敏感性。此外，表达shUSP 14的NSCLC细胞显示出增加的NHEJ效率，如通过关键NHEJ蛋白的染色质募集、NHEJ报告基因测定以及通过53 BP 1和pS2056-DNA-PKcs增加的IR诱导的病灶形成所指示的。相反，表达shUSP 14的NSCLC细胞显示RPA 32和BRCA 1病灶形成减少，表明HR缺陷。这些发现确定USP 14是DSB修复对放疗的反应的重要决定因素，也是NSCLC放射增敏的有希望的靶点。
Non-small cell lung cancer (NSCLC) represents ~85% of the lung cancer cases. Despite recent advances in NSCLC treatment, the five-year survival rate is still around 23%. Radiotherapy is indicated in the treatment of both early and advanced stage NSCLC; however, treatment response in patients is heterogeneous. Thus, identification of new and more effective treatment combinations is warranted. We have identified Ubiquitin-specific protease 14 (USP14) s a regulator of major double-strand break (DSB) repair pathways in response to ionizing radiation (IR) by its impact on both non-homologous end joining (NHEJ) and homologous recombination (HR) in NSCLC. USP14 is a proteasomal deubiquitinase. IR treatment increases levels and DSB recruitment of USP14 in NSCLC cell lines. Genetic knockdown, using shUSP14 expression or pharmacological inhibition of USP14, using IU1, increases radiosensitization in NSCLC cell lines, as determined by a clonogenic survival assay. Moreover, shUSP14-expressing NSCLC cells show increased NHEJ efficiency, as indicated by chromatin recruitment of key NHEJ proteins, NHEJ reporter assay, and increased IR-induced foci formation by 53BP1 and pS2056-DNA-PKcs. Conversely, shUSP14-expressing NSCLC cells show decreased RPA32 and BRCA1 foci formation, suggesting HR-deficiency. These findings identify USP14 as an important determinant of DSB repair in response to radiotherapy and a promising target for NSCLC radiosensitization.
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影响因子：
7.2
作者：
Prakash R;Zhang Y;Feng W;Jasin M
通讯作者：
Jasin M
影响因子：
5.6
作者：
de Poot SAH;Tian G;Finley D
通讯作者：
Finley D
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.96.5.1921
发表时间：
1999-03-02
影响因子：
11.1
作者：
Raderschall, E;Golub, EI;Haaf, T
通讯作者：
Haaf, T
影响因子：
16.6
作者：
Riaz N;Blecua P;Lim RS;Shen R;Higginson DS;Weinhold N;Norton L;Weigelt B;Powell SN;Reis-Filho JS
通讯作者：
Reis-Filho JS