USP7 is a novel deubiquitinase sustaining PLK1 protein stability and regulating chromosome alignment in mitosis.
Open accessAbstract
Background: The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. Methods: Cell viability or clonogenicity was tested by violet crystal assay. Cell apoptosis or cell cycle was analyzed by flow cytometry, and chromosome misalignment was observed by a fluorescent microscopy. The protein interaction of PLK1 and USP7 was detected by tandem affinity purification and high throughput proteomics, and further confirmed by co-immunoprecipitation, GST pull-down and protein co-localization. The correlation between USP7 level of tumor tissues and taxane-resistance was evaluated. Results: Pharmacological USP7 inhibition by P5091 retarded cell proliferation and induced cell apoptosis. Further studies showed that P5091 induced cell cycle arrest at G2/M phase, and particularly induced chromosome misalignment, indicating the key roles of USP7 in mitosis. USP7 protein was detected in the PLK1-interacted protein complex. USP7 interacts with PLK1 protein through its PBD domain by catalytic activity. USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway. By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival. Both USP7 and PLK1 were overexpressed in taxane-resistant cancer cells, and negatively correlated with the MP scores in tumor tissues. Either USP7 or PLK1 knockdown by RNAi significantly sensitized taxane-resistant cells to taxane cell killing. Conclusion: This is the first report that PLK1 is a novel substrate of USP7 deubiquitinase, and that USP7 sustained the protein stability of PLK1. USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.
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Several well-characterized USP7 substrates, including p53, PHF8, and PLK1, are known to be key regulators of cell cycle progression and cellular proliferation-processes fundamental to HSC maintenance.
“several well-characterized USP7 substrates, including p53 30, PHF8 31, and PLK1 32, are known to be key regulators of cell cycle progression and cellular proliferation—processes fundamental to HSC maintenance.”
From USP7 sustains hematopoietic stem cell homeostasis partially via PU.1 stabilization (2026) · cites this paper as [32]
Another proposed use for USP7 inhibitors is in sensitizing taxane-resistant tumors to taxane therapies.
“Another proposed use for USP7 inhibitors is in sensitizing taxane-resistant tumors to taxane therapies (Giovinazzi et al., 2013; Zhang et al., 2016; Peng et al., 2019).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Peng et al., 2019
USP7 inhibitors simultaneously promote p53 activation via the induction of genomic instability.
“In addition, USP7 inhibitors simultaneously promote p53 activation via the induction of genomic instability (Giovinazzi et al., 2013, 2014; Peng et al., 2019).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Peng et al., 2019
USP7 inhibition causes mitotic stress as a result of Plk1 depletion, driving cells towards apoptotic cell-death.
“For instance, as we discussed in the Mitosis section above, USP7 inhibition causes mitotic stress as a result of Plk1 depletion, driving cells towards apoptotic cell-death (Peng et al., 2019).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Peng et al., 2019
By inducing PLK1 degradation, USP7 inhibition with P5091 sensitizes taxane-resistant cancer cells to paclitaxel and docetaxel and triggers apoptotic cell death.
“By inducing PLK1 degradation, USP7 inhibition with P5091 was, however, found to sensitize taxane-resistant cancer cells to paclitaxel and docetaxel and to trigger apoptotic cell death (Peng et al., 2019).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Peng et al., 2019
USP7 and PLK1 were found to correlate in tissue sections of primary breast cancer and to be highly expressed in taxane-resistant tumors.
“Indeed, USP7 and PLK1 were found to correlate in tissue sections of primary breast cancer and to be highly expressed in taxane-resistant tumors (Peng et al., 2019).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Peng et al., 2019
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References 34 · Cited by 54
- Authors
- Peng, Y., Liu, Y., Gao, Y., Yuan, B., Qi, X., Fu, Y., Zhu, Q., Cao, T., Zhang, S., Yin, L., & Li, X.
- Affiliations
- Central South University (CN)
- Corresponding author
- Li, Xiong
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2019-11-15
- Volume
- 38
- Issue
- 1
- Pages
- 468-468
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC6858727
- OpenAlex
- W2986255163
- Cited by
- 54
- References
- 34
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 12 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 1
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (NSFC, 81572542, NSFC, 81874196)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- USP7, deubiquitinase, PLK1, protein stability, chromosome misalignment, mitosis, taxane resistance, G2/M cell cycle arrest, apoptosis, oncogenes
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Docetaxel, Polo-Like Kinase 1, Chromosomes, Chromosomes, Human, Humans, Male, Mitosis, Nasopharyngeal Neoplasms, Prostatic Neoplasms, Protease Inhibitors, Proto-Oncogene Proteins, Thiophenes, Transfection, Signal Transduction, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Drug Resistance, Neoplasm, Protein Stability, HEK293 Cells, G2 Phase Cell Cycle Checkpoints, M Phase Cell Cycle Checkpoints
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