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USP22通过调节γH2AX介导的DNA损伤修复和Ku70/Bax介导的凋亡诱导肺腺癌顺铂耐药。

USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating γH2AX-Mediated DNA Damage Repair and Ku70/Bax-Mediated Apoptosis.

作者信息

Wang Aman, Ning Zhen, Lu Chang, Gao Wei, Liang Jinxiao, Yan Qiu, Tan Guang, Liu Jiwei

机构信息

Department of Oncology, The First Affiliated Hospital, Dalian Medical UniversityDalian, China.

Department of Hepatobiliary Surgery, The First Affiliated Hospital, Dalian Medical UniversityDalian, China.

出版信息

Front Pharmacol. 2017 May 17;8:274. doi: 10.3389/fphar.2017.00274. eCollection 2017.

DOI:10.3389/fphar.2017.00274
PMID:28567015
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5434448/
Abstract

Resistance to platinum-based chemotherapy is one of the most important reasons for treatment failure in advanced non-small cell lung cancer, but the underlying mechanism is extremely complex and unclear. The present study aimed to investigate the correlation of ubiquitin-specific peptidase 22 (USP22) with acquired resistance to cisplatin in lung adenocarcinoma. In this study, we found that overexpression of USP22 could lead to cisplatin resistance in A549 cells. USP22 and its downstream proteins γH2AX and Sirt1 levels are upregulated in the cisplatin- resistant A549/CDDP cell line. USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A. In addition, USP22 decreases the acetylation of Ku70 by stabilizing Sirt1, thus inhibiting Bax-mediated apoptosis and inducing cisplatin resistance. The cisplatin sensitivity in cisplatin-resistant A549/CDDP cells was restored by USP22 inhibition and . In summary, our findings reveal the dual mechanism of USP22 involvement in cisplatin resistance that USP22 can regulate γH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. USP22 is a potential target in cisplatin-resistant lung adenocarcinoma and should be considered in future therapeutic practice.

摘要

对铂类化疗药物耐药是晚期非小细胞肺癌治疗失败的最重要原因之一，但其潜在机制极其复杂且尚不清楚。本研究旨在探讨泛素特异性蛋白酶22（USP22）与肺腺癌顺铂获得性耐药的相关性。在本研究中，我们发现USP22的过表达可导致A549细胞对顺铂耐药。在顺铂耐药的A549/CDDP细胞系中，USP22及其下游蛋白γH2AX和Sirt1的水平上调。USP22通过去泛素化组蛋白H2A促进组蛋白H2AX的磷酸化，增强DNA损伤修复并诱导顺铂耐药。此外，USP22通过稳定Sirt1降低Ku70的乙酰化，从而抑制Bax介导的凋亡并诱导顺铂耐药。通过抑制USP22恢复了顺铂耐药的A549/CDDP细胞对顺铂的敏感性。总之，我们的研究结果揭示了USP22参与顺铂耐药的双重机制，即USP22可调节γH2AX介导的DNA损伤修复和Ku70/Bax介导的凋亡。USP22是顺铂耐药肺腺癌的一个潜在靶点，应在未来的治疗实践中予以考虑。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/62ed5f29b386/fphar-08-00274-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/53639005ef9c/fphar-08-00274-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/20d9d544e267/fphar-08-00274-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/9c3ae56945e9/fphar-08-00274-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/4bd7832e34e0/fphar-08-00274-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/3a9790abbf5b/fphar-08-00274-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/62ed5f29b386/fphar-08-00274-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/53639005ef9c/fphar-08-00274-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/20d9d544e267/fphar-08-00274-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/9c3ae56945e9/fphar-08-00274-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/4bd7832e34e0/fphar-08-00274-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/3a9790abbf5b/fphar-08-00274-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b95/5434448/62ed5f29b386/fphar-08-00274-g006.jpg

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