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FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC

Francesco Morra1,2, Chiara Luise1, Francesco Merolla1,3

  • 1Istituto per l'Endocrinologia e l'Oncologia Sperimentale "Gaetano Salvatore", CNR, Napoli, Italy.

Oncotarget
|April 18, 2015
PubMed

Insights

The CCDC6 protein

Area of Science:

  • Cellular Biology
  • Molecular Oncology

Background:

  • CCDC6 protein loss or inactivation promotes tumor progression.
  • Low CCDC6 protein levels in non-small cell lung cancer (NSCLC) correlate with poor prognosis.
  • Mechanisms driving variable CCDC6 levels in tumors remain unclear.

Purpose of the Study:

  • Investigate the mechanisms regulating CCDC6 protein levels.
  • Determine the role of cell cycle and post-translational modifications in CCDC6 stability.
  • Explore the impact of CCDC6 turnover on cellular behavior and drug response.

Main Methods:

  • Cell cycle analysis to assess CCDC6 protein levels and phosphorylation.
  • Ubiquitination assays to identify CCDC6 degradation pathways.
  • Pharmacological inhibition of mitotic kinases and de-ubiquitinase USP7.

Main Results:

  • CCDC6 protein levels and phosphorylation exhibit cell cycle-dependent variation, peaking in G2 and decreasing in mitosis.
  • CCDC6 instability during M phase is mediated by mitotic kinases and FBXW7 E3 ubiquitin ligase recruitment via degron motifs.
  • The de-ubiquitinase USP7 fine-tunes CCDC6 stability, influencing cell behavior and drug sensitivity.

Conclusions:

  • CCDC6 turnover is tightly regulated by cell cycle-dependent post-translational modifications and protein-protein interactions.
  • Impaired CCDC6 turnover may explain variable protein levels in tumors, impacting prognosis.
  • Understanding CCDC6 regulation is crucial for optimizing personalized cancer therapies.
Keywords:
CCDC6FBXW7USP7cisplatinummitotic kinases

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