USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase

Cell Death Differ. 2013 May;20(5):721-31. doi: 10.1038/cdd.2012.169. Epub 2013 Jan 25.

Abstract

A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Aurora Kinases
  • Benzazepines / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Bridged-Ring Compounds / pharmacology*
  • Bridged-Ring Compounds / therapeutic use
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Co-Repressor Proteins
  • Cyclin B / metabolism
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Mitosis
  • Molecular Chaperones
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / metabolism*
  • Poly-ADP-Ribose Binding Proteins
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Taxoids / pharmacology*
  • Taxoids / therapeutic use
  • Tumor Suppressor Protein p53
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Protein Ligases
  • Ubiquitin-Specific Peptidase 7

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Benzazepines
  • Bridged-Ring Compounds
  • Cell Cycle Proteins
  • Co-Repressor Proteins
  • Cyclin B
  • DAXX protein, human
  • MLN8054
  • Molecular Chaperones
  • Neoplasm Proteins
  • Nuclear Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA, Small Interfering
  • Taxoids
  • Tumor Suppressor Protein p53
  • taxane
  • CHFR protein, human
  • Ubiquitin-Protein Ligases
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7