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

Abstract

Prior studies have noted that Zinc nger E-box binding homeobox 1 (ZEB1) is a master transcription regulator, affecting the expression of nearly 2,000 genes in breast cancer cells, especially in epithelial-mesenchymal transition (EMT) process. In this study, we found that ZEB1 directly regulated Glutathione peroxidase 4 (GPX4) transcriptions, which was closely related to tumor reactive oxygen species (ROS) metabolism. We selected two human breast cancer cell linesMDA-MB-231 and MCF7 for ROS test, PCR, immuno uorescence, western blot, ChIP, luciferase assay and enzyme assay. The conclusions continue to be supported in mouse models and bioinformatics analysis. We found that ZEB1 directly bound to GPX4 promoter E-box motif (CANNTG) to inhibit GPX4 transcription, which contributing to ROS accumulation and tumorigenesis in breast cancer.

Regulatory pathways and drugs associated with ferroptosis in tumors

“…Such as ferrostatin-1 and liproxstatin-1, both inhibitors work by inhibiting lipid peroxides, thereby inhibiting ferroptosis in tumor cells [ 188 , 189 ]. Vitamin E, a fat-soluble Vitamin, is one of the main antioxidants and also inhibits ferroptosis by inhibiting the production of lipid peroxides [ 190 ]. Deferoxamine (DFO) [ 187 ], Ciclopirox [ 191 ], and Deferiprone [ 192 ] inhibit ferroptosis by deplete iron.…”

Efficient Magnetic Nanocatalyst-Induced Chemo- and Ferroptosis Synergistic Cancer Therapy in Combination with T1–T2 Dual-Mode Magnetic Resonance Imaging Through Doxorubicin Delivery

“…In addition, the expression of cleaved caspase-3 in cells dramatically increased after ipGdIO-Dox treatment, further confirming that ipGdIO-Dox had the strongest ability to kill cancer cells. In addition, GPX4 protein could effectively eliminate cellular ROS through converting GSH into GSSG and then avoid ferroptosis. , Therefore, the expression of GPX4 was considered to be an important ferroptotic marker. In Figure c, the expression of GPX4 significantly decreased after pGdIO-Dox treatment, confirming the presence of ferroptosis.…”

“…In addition, GPX4 protein could effectively eliminate cellular ROS through converting GSH into GSSG and then avoid ferroptosis. 39,40 Therefore, the expression of GPX4 was considered to be an important ferroptotic marker. In Figure 4c, the expression of GPX4 significantly decreased after pGdIO-Dox treatment, confirming the presence of ferroptosis.…”

Bilateral varicocele leads to ferroptosis, pyroptosis and necroptosis of human spermatozoa and affects semen quality in infertile men

“…One study have identified that iPLA2β was a critical regulator for p53-driven ferroptosis upon ROS induced stress (Chen et al, 2021). ZEB1 is a master transcription regulator that affects ROS and oxidative stress Frontiers in Cell and Developmental Biology frontiersin.org metabolism (Han et al, 2021). A recent study indicated that ZEB1 directly inhibited GPX4 transcription, thus contributing to ROS accumulation (Han et al, 2021).…”

“…Ferroptosis is different from apoptosis, autophagy, and necrosis in morphology, metabolism, and biochemistry. It has been shown that the ferroptosis is caused by the imbalance between ROS production and peroxidation-antioxidant system ( Han et al, 2021 ). Importantly, Imai et al showed that GPX4 was strongly expressed in the testis and spermatozoa, and that 30% of the infertile men diagnosed with oligoasthenozoospermia had significantly lower GPX4 expression in spermatozoa ( Imai et al, 2001 ).…”