Abstract
Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins / physiology*
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Breast Neoplasms / metabolism*
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Breast Neoplasms / mortality
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Checkpoint Kinase 1
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DNA Damage*
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DNA Repair
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Epithelial-Mesenchymal Transition
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Female
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Gene Expression Regulation, Neoplastic
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HEK293 Cells
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HeLa Cells
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Kaplan-Meier Estimate
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MCF-7 Cells
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Mice
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Mice, Nude
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein Kinases / metabolism*
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Protein Stability
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Radiation Tolerance
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Twist-Related Protein 1 / genetics
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Twist-Related Protein 1 / metabolism
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Ubiquitin Thiolesterase / metabolism
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Ubiquitin-Specific Peptidase 7
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Ubiquitination
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Up-Regulation
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Xenograft Model Antitumor Assays
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Zinc Finger E-box-Binding Homeobox 1
Substances
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Homeodomain Proteins
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Nuclear Proteins
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Snail Family Transcription Factors
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TWIST1 protein, human
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Transcription Factors
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Twist-Related Protein 1
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1
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Protein Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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USP7 protein, human
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Ubiquitin Thiolesterase
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Ubiquitin-Specific Peptidase 7