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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Movement
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Cyclin-Dependent Kinase 4 / antagonists & inhibitors
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Cyclin-Dependent Kinase 4 / genetics*
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Cyclin-Dependent Kinase 4 / metabolism
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Cyclin-Dependent Kinase 6 / antagonists & inhibitors
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Cyclin-Dependent Kinase 6 / genetics*
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Cyclin-Dependent Kinase 6 / metabolism
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Disease Models, Animal
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Endopeptidases / genetics*
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Endopeptidases / metabolism
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Leupeptins / pharmacology
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Liver Neoplasms / genetics*
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Liver Neoplasms / metabolism
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Liver Neoplasms / prevention & control
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Liver Neoplasms / secondary
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary
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MCF-7 Cells
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Mice
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / prevention & control
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Ovarian Neoplasms / secondary
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Piperazines / pharmacology
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Pyridines / pharmacology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Snail Family Transcription Factors / genetics
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Snail Family Transcription Factors / metabolism
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Triple Negative Breast Neoplasms / genetics*
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Leupeptins
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Piperazines
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Pyridines
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RNA, Small Interfering
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SNAI1 protein, human
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Snail Family Transcription Factors
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CDK4 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase 6
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Endopeptidases
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USP17L2 protein, human
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palbociclib
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde