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COP9 signalosome subunit 5 regulates cancer metastasis by deubiquitinating SNAIL

Kensuke Watanabe1, Satoru Yokoyama1, Naoki Kaneto1

  • 1Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.

Oncotarget
|May 15, 2018
PubMed

Insights

COP9 signalosome subunit 5 (COPS5) deubiquitinates and stabilizes the transcription factor SNAIL, a key driver of cancer metastasis. Inhibiting COPS5 reduced lung cancer cell metastasis, suggesting COPS5 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Cancer metastasis is a primary cause of cancer-related mortality.
  • The transcription factor SNAIL is crucial for cancer metastasis and progression.
  • SNAIL's stability is regulated by the ubiquitin-proteasome system, involving ubiquitin ligases and deubiquitinating enzymes (DUBs).

Purpose of the Study:

  • To identify the deubiquitinating enzyme (DUB) responsible for regulating SNAIL stability.
  • To investigate the role of COP9 signalosome subunit 5 (COPS5) as a DUB for SNAIL.
  • To evaluate the therapeutic potential of targeting COPS5 in lung cancer metastasis.

Main Methods:

  • siRNA library screening to identify SNAIL-interacting DUBs.
  • In vitro and in vivo assays to assess lung cancer cell metastatic potential upon COPS5 downregulation.
  • Co-immunoprecipitation to confirm COPS5-SNAIL binding.
  • Tissue microarray analysis of clinical lung adenocarcinoma samples.

Main Results:

  • COP9 signalosome subunit 5 (COPS5) was identified as a deubiquitinating enzyme of SNAIL.
  • COPS5 downregulation significantly decreased SNAIL expression and impaired lung cancer cell metastasis in vitro and in vivo.
  • COPS5 directly binds to SNAIL, stabilizing its expression through deubiquitination.
  • A positive correlation between COPS5 and SNAIL expression was observed in clinical lung adenocarcinoma tissues.

Conclusions:

  • COP9 signalosome subunit 5 (COPS5) functions as a deubiquitinating enzyme that stabilizes SNAIL.
  • COPS5 plays a critical role in promoting lung cancer metastasis by regulating SNAIL.
  • COPS5 represents a potential therapeutic target for inhibiting cancer metastasis.
Keywords:
COPS5SNAILdeubiquitinationlung cancermetastasis

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