1. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition.
- Author
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Schwab A, Rao Z, Zhang J, Gollowitzer A, Siebenkäs K, Bindel N, D'Avanzo E, van Roey R, Hajjaj Y, Özel E, Armstark I, Bereuter L, Su F, Grander J, Bonyadi Rad E, Groenewoud A, Engel FB, Bell GW, Henry WS, Angeli JPF, Stemmler MP, Brabletz S, Koeberle A, and Brabletz T
- Subjects
- Humans, Cell Line, Tumor, Lipogenesis, Gene Expression Regulation, Neoplastic, Fatty Acid Desaturases metabolism, Fatty Acid Desaturases genetics, Animals, Neoplasms pathology, Neoplasms metabolism, Neoplasms genetics, Coenzyme A Ligases metabolism, Coenzyme A Ligases genetics, Transforming Growth Factor beta metabolism, Delta-5 Fatty Acid Desaturase, Drug Resistance, Neoplasm, Fatty Acid Synthase, Type I metabolism, Fatty Acid Synthase, Type I genetics, Ferroptosis, Zinc Finger E-box-Binding Homeobox 1 metabolism, Zinc Finger E-box-Binding Homeobox 1 genetics, Epithelial-Mesenchymal Transition, Phospholipids metabolism, Stearoyl-CoA Desaturase metabolism, Stearoyl-CoA Desaturase genetics
- Abstract
Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic enzymes (SCD and FADS2) allows the manipulation of ferroptosis sensitivity preferentially in high-Zeb1-expressing cancer cells. Our data are of potential translational relevance and suggest a combination of ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1., (© 2024. The Author(s).)
- Published
- 2024
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