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

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 (DDR). Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of ATM and upregulation of ZEB1, and ZEB1 promotes tumor cell radioresistance in vitro and in vivo. Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate 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 as the mechanism underlying the association between EMT and radioresistance.