Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance

Summary

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and most patients die within one year after diagnosis. This cancer is resistant to almost all current therapies, so there is an urgent need to identify novel druggable targets. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that functions in carcinogenesis, but its role in PDAC is unknown. Our experiments indicated that several subtypes of PDAC cells are sensitive to USP7 inhibition. In particular, pharmaceutical inhibition of USP7 by the small molecule P22077 attenuated PDAC cell growth and induced cell death in vitro and in vivo. Pharmaceutical inhibition of USP7 in P22077-resistant PDAC cells allowed them to overcome chemoresistance. Genetic silencing experiments supported the importance of USP7 in the pathogenesis of PDAC. In particular, genetic disruption of USP7 greatly reduced cell proliferation and chemoresistance in vitro and prevented PDAC growth in vivo. Protein profiling by mass spectrometry (MS) indicated USP7 was associated 4 ontology terms: translation, localization and protein transporting, nucleotide or ribonucleotide binding, and ubiquitin-dependent catabolic processes. Puromycin labeling indicated that P22077 greatly reduced protein synthesis, and transcriptional analysis indicated that P22077 significantly altered the extracellular space matrix. In summary, we provided multiple lines of evidence which indicate that USP7 plays a critical role in PDAC, and may therefore be a suitable target for treatment of this cancer.

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Data availability

The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request.

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Funding

The work was supported by the National Natural Science Foundation of China (81873531; 81600386; 81572397); the Distinguished Professorship Program of Jiangsu Province to Renfang Mao; the Distinguished Professorship Program of Jiangsu Province to Yihui Fan; the Natural Science Foundation of Jiangsu Province (Grant No: BK20181458); and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_2406).

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H Chen, Y FAN, G Zhou and R Mao conceived the idea and designed the research. H Chen, X Zhu, P Ma, E Zhang and Z Wang performed in vitro experiments. H Chen and X Zhu performed mice xenograft experiments. H Chen, Rong Sun, Y Fan, G Zhou and R Mao analyzed the data. H Chen, Yihui Fan, G Zhou and R Mao wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Guoxiong Zhou or Renfang Mao.

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The abstract of this manuscript was presented at the Asian Pacific Digestive Week 2019 (APDW 2019) and published in the society’s journal “Journal of Gastroenterology and Hepatology” (https://onlinelibrary.wiley.com/doi/full/10.1111/jgh.14879). All authors declare no conflict of interest.

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The protocols used for animal studies were approved by the Laboratory Animal Center of Nantong University, and all procedures followed internationally accepted principles and the Guidelines of the Animal Care and Use.

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Chen, H., Zhu, X., Sun, R. et al. Ubiquitin-specific protease 7 is a druggable target that is essential for pancreatic cancer growth and chemoresistance. Invest New Drugs (2020). https://doi.org/10.1007/s10637-020-00951-0

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Keywords

  • Pancreatic ductal adenocarcinoma
  • USP7
  • chemoresistance
  • translation