CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1

Nat Commun. 2017 Jan 9;8:13923. doi: 10.1038/ncomms13923.

Abstract

Tumour metastasis, the spread of cancer cells from the original tumour site followed by growth of secondary tumours at distant organs, is the primary cause of cancer-related deaths and remains poorly understood. Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-negative breast cancer model, without affecting tumour growth. Mechanistically, we identify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a key factor promoting epithelial-mesenchymal transition and breast cancer metastasis. Overall, our study establishes the CDK4/6-DUB3 axis as an important regulatory mechanism of breast cancer metastasis and provides a rationale for potential therapeutic interventions in the treatment of breast cancer metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / genetics*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / genetics*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Disease Models, Animal
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Leupeptins / pharmacology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • MCF-7 Cells
  • Mice
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / prevention & control
  • Ovarian Neoplasms / secondary
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Snail Family Transcription Factors / genetics
  • Snail Family Transcription Factors / metabolism
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Leupeptins
  • Piperazines
  • Pyridines
  • RNA, Small Interfering
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Endopeptidases
  • USP17L2 protein, human
  • palbociclib
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde