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Nat Cell Biol. 2014 Sep;16(9):864-75. doi: 10.1038/ncb3013. Epub 2014 Aug 3.

ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.

Author information

1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
3
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, USA.
6
Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA.
7
1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 402, Taiwan [3] Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
8
1] Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.

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.

PMID:
25086746
PMCID:
PMC4150825
DOI:
10.1038/ncb3013
[Indexed for MEDLINE]
Free PMC Article

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