ZEB1 inhibition sensitizes cells to the ATR inhibitor VE-821 by abrogating epithelial-mesenchymal transition and enhancing DNA damage.
The ataxia-telangiectasia-mutated (ATM) and rad3-related (ATR) checkpoint pathway plays an essential role in modulating cellular responses to replication stress and DNA damage to maintain genomic stability. In various tumors, cancer cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. ATR inhibitors sensitize multiple tumor cell types to radiation and DNA-damaging agents, but application of an ATR inhibitor alone shows limited efficacy. In the present study, we investigated the role of epithelial-to-mesenchymal transition (EMT) and the EMT transcription factor ZEB1 in regulating cell sensitivity to the ATR inhibitor VE-821. We found that VE-821 induced EMT with concomitant ZEB1 upregulation and promoted migration in cells in which the anti-proliferative effect of VE-821 was limited. Knocking down ZEB1 using siRNA partially reversed VE-821-induced EMT, and sensitized cells to VE-821 via effective attenuation of migration and AKT/ERK signaling. Moreover, ZEB1 inhibition promoted Chk1 phosphorylation and induced S-phase arrest by enhancing TopBP1 expression, which suggests a distinctive modulatory effect of ZEB1 on Chk1. Finally, combining VE-821 with ZEB1 inhibition enhanced DNA damage accumulation. These results demonstrate that EMT represents a novel mechanism for limiting the effectiveness of an ATR inhibitor, and thus suggest that ZEB1 inhibition might represent a new approach to increasing the efficiency of, or reversing resistance to, ATR inhibitors.
['Song|Na|N|', 'Jing|Wei|W|', 'Li|Ce|C|', 'Bai|Ming|M|', 'Cheng|Yu|Y|', 'Li|Heming|H|', 'Hou|Kezuo|K|', 'Li|Yanrong|Y|', 'Wang|Kai|K|', 'Li|Zhi|Z|', 'Liu|Yunpeng|Y|', 'Qu|Xiujuan|X|', 'Che|Xiaofang|X|']
D064007:Ataxia Telangiectasia Mutated Proteins D015820:Cadherins D002352:Carrier Proteins D045744:Cell Line, Tumor D002465:Cell Movement D002470:Cell Survival D000071877:Checkpoint Kinase 1 D004249:DNA Damage D004268:DNA-Binding Proteins D058750:Epithelial-Mesenchymal Transition D006801:Humans D009687:Nuclear Proteins D010766:Phosphorylation D011719:Pyrazines D034622:RNA Interference D034741:RNA, Small Interfering D059807:S Phase Cell Cycle Checkpoints D013450:Sulfones D015854:Up-Regulation D000071799:Zinc Finger E-box-Binding Homeobox 1
ZEB1 sensitivity ATR ATR inhibitor DNA damage EMT Chk1