Oncotarget

Research Papers:

ISG15 silencing increases cisplatin resistance via activating p53-mediated cell DNA repair

Yi Huo, Zhaoyun Zong, Qingtao Wang, Zhenyu Zhang and Haiteng Deng _

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Oncotarget. 2017; 8:107452-107461. https://doi.org/10.18632/oncotarget.22488

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Abstract

Yi Huo1,*, Zhaoyun Zong1,*, Qingtao Wang2, Zhenyu Zhang2 and Haiteng Deng1

1MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China

2Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China

*Co-first authors

Correspondence to:

Haiteng Deng, email: dht@tsinghua.edu.cn

Keywords: cancer cells; drug-resistance; proteomics; ISG15; cisplatin

Received: June 23, 2017     Accepted: October 28, 2017     Published: November 18, 2017

ABSTRACT

Tumor cells frequently evolved resistance to cisplatin that greatly compromises the efficacy of chemotherapy. Identification of the mechanisms underlying drug resistance is important for developing new therapeutic approaches. ISG15 is found to be elevated in many human carcinomas and cancer cell lines. Here, we identified that the expressions of ISG15 and ISG15-conjugating system were downregulated in drug resistant A549/DDP cells compared to drug sensitive A549 cells. Silencing of ISG15 robustly elevated the resistance to cisplatin, suggesting ISG15 plays an important role in cisplatin resistance. Quantitative proteomics identified 1296 differentially expressed proteins between the control and ISG15 knockdown cells, showing that ISG15 silencing upregulated proteins in p53 pathway, adherens junction and nucleotide excision repair (NER) pathway. We also found that ISG15 silencing induced cell cycle arrest through stabilizing p53 and increasing HnRNP K expression, which allowed the prolonged time for cells to repair cisplatin-damaged DNA. Taken together, we proved that ISG15 downregulation activated the DNA damage/repair pathway to enhance cisplatin resistance in tumor cells.


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