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

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Epithelial-mesenchymal transition (EMT) is linked to breast cancer stem cell traits like chemoresistance and radioresistance.
• The precise role of EMT or its regulators in conferring these resistance properties remains unclear.

Purpose of the Study:

• To identify specific regulators of EMT involved in breast cancer radioresistance.
• To elucidate the molecular mechanisms by which EMT regulators influence DNA damage response and radiosensitivity.

Main Methods:

• Identification of EMT-inducing transcription factors.
• Analysis of radioresistant breast cancer cell subpopulations.
• In vitro and in vivo studies of tumor cell radiosensitivity.
• Investigation of protein-protein interactions and post-translational modifications (phosphorylation, ubiquitination).

Main Results:

• Zinc finger E-box binding homeobox 1 (ZEB1), an EMT-inducing transcription factor, was identified as a key regulator of radiosensitivity.
• ZEB1 upregulation and ATM kinase hyperactivation were observed in radioresistant breast cancer cells.
• ATM phosphorylates and stabilizes ZEB1, which then interacts with USP7 to deubiquitylate and stabilize CHK1.
• This ZEB1-mediated pathway promotes homologous recombination DNA repair, enhancing resistance to ionizing radiation.

Conclusions:

• ZEB1 directly contributes to tumor cell radioresistance.
• ZEB1 acts as an ATM substrate, linking ATM signaling to CHK1 stabilization and DNA repair.
• These findings reveal a molecular mechanism connecting EMT to radioresistance in breast cancer.