ZEB1 induces ROS generation through directly promoting MCT4 transcription to facilitate breast cancer

Purpose: Transcription factor zinc finger E-box binding homeobox 1(ZEB1) was well-known as a transcription factor in epithelial-mesenchymal transition (EMT) process of Cancer, but little is known about its role in Cancer metabolism. We found metabolism-related gene Monocarboxylate Transporter 4 (MCT4) contained E-box motifs in its promoter region, which is the potential binding site of ZEB1. Thus, the correlation between ZEB1 and MCT4 was also investigated in this study.

Methods: Two human breast Cancer cell lines MDA-MB-231 and MCF7 were used for ZEB1 and MCT4 expression by double fluorescence staining, ChIP as well as luciferase reporter. ROS levels were revealed by DCFDA and DHE fluorescence probes. The role of ZEB1/MCT4/ROS/Autophagy was also determined in xenograft tumor mice model.

Results: MCT4 and ZEB1 were synchronously expressed in two types of breast Cancer cells. Moreover, ZEB1 positively regulated the expression and the function of MCT4 through binding to the E-box motifs in MCT4' promoter. In addition, the in vitro and in vivo experiments showed that ZEB1/MCT4 in synergy promoted the growth of breast Cancer through ROS generation and Autophagy, which can be reversed by a MCT4 Inhibitor, 7ACC1.

Conclusion: ZEB1 directly binds to E-box elements of MCT4 promoter and enhance MCT4 expression, inducing ROS accumulation, which cooperatively resulting in breast Cancer growth and shorten survival. Our findings provide a theoretical basis for interfering the metabolism in breast Cancer therapeutics.