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

Peijing Zhang, Yongkun Wei, L. i. Wang, Bisrat G. Debeb, Yuan Yuan, Jinsong Zhang, Jingsong Yuan, Min Wang, Dahu Chen, Yutong Sun, Wendy A. Woodward, Yongqing Liu, Douglas C. Dean, Han Liang, Ye Hu, K. Kian Ang, Mien Chie Hung, Junjie Chen, Li Ma

Research output: Contribution to journalArticle

191 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)864-875
Number of pages12
JournalNature Cell Biology
Volume16
Issue number9
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Cell Biology

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    Zhang, P., Wei, Y., Wang, L. I., Debeb, B. G., Yuan, Y., Zhang, J., Yuan, J., Wang, M., Chen, D., Sun, Y., Woodward, W. A., Liu, Y., Dean, D. C., Liang, H., Hu, Y., Ang, K. K., Hung, M. C., Chen, J., & Ma, L. (2014). ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nature Cell Biology, 16(9), 864-875. https://doi.org/10.1038/ncb3013