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ZEB1 directly inhibits GPX4 transcription contributing to ROS accumulation in breast cancer cells

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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Prior studies have noted that zinc finger E-box binding homeobox 1 (ZEB1) is a master transcription regulator, affecting the expression of nearly 2000 genes in breast cancer cells, especially in the epithelial–mesenchymal transition (EMT) process. We now tested the role of ZEB1 on the oxidative stress of cancer cells and explored its possible mechanisms.

Methods

Two human breast cancer cell lines MDA-MB-231 and MCF7 were selected for the ROS test, PCR, immunofluorescence, Western blot, chromatin immunoprecipitation assay, luciferase assay, and enzyme assay. Mouse models experiments and bioinformatics analysis were conducted to test the indicated molecules.

Results

We observed ZEB1 could inhibit GPX4 transcription by binding to the E-box motifs and promote breast cancer progression by accumulating intracellular ROS. From the perspective of ROS clearance, Vitamin E enhanced GPX4 function to consume L-glutathione and eliminated excess intracellular ROS.

Conclusions

ZEB1 could not only regulate EMT, but also inhibit GPX4 transcription by binding to the E-box motif. It was important to note that the ZEB1/GPX4 axis had a therapeutic effect on breast cancer metabolism.

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Acknowledgements

This study was supported by grants from Natural Science Foundation of China (No.31770968 and 31800661), the Open Project Program of Key Laboratory for Tumor Precision Medicine of Shaanxi Province (KLTPM-SX2017-A3& KLTPM-SX2018-B1), and the Open Project Program of the Chongqing TCM key Laboratory for Metabolic Disease (Chongqing Medical University).

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Authors and Affiliations

  1. School of Medicine, Nankai University, Tianjin, 300071, China

    Xianxian Duan, Zhanzhao Liu, Yaping Long, Chang Liu, Jing Zhou, Junfang Qin & Yue Wang

  2. Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Hospital of Stomatology, Nankai University, Tianjin, 300041, China

    Yue Wang

  3. State Key Laboratory of Medicinal Chemical Biology & College of Pharmacy, Nankai University, Tianjin, 300354, China

    Xiao Han

  4. Institute of Disaster Medicine, Tianjin University, Tianjin, 300072, China

    Ning Li

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  1. Xiao Han
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Han, X., Duan, X., Liu, Z. et al. ZEB1 directly inhibits GPX4 transcription contributing to ROS accumulation in breast cancer cells. Breast Cancer Res Treat 188, 329–342 (2021). https://doi.org/10.1007/s10549-021-06301-9

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