Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition

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 F, Bell GW, Henry WS, Angeli JPF, Stemmler MP, Brabletz S, Koeberle A, Brabletz T (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Nature Cell Biology Nature Research

DOI: 10.1038/s41556-024-01464-1

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.

Authors with CRIS profile

Arwin Groenewoud Department of Nephropathology Felix Engel Professur für Experimentelle Nieren- und Kreislaufforschung

Involved external institutions

Leopold-Franzens-Universität Innsbruck / University of Innsbruck AT Austria (AT) Massachusetts Institute of Technology (MIT) US United States (USA) (US) Julius-Maximilians-Universität Würzburg DE Germany (DE)

How to cite

APA:

Schwab, A., Rao, Z., Zhang, J., Gollowitzer, A., Siebenkäs, K., Bindel, N.,... Brabletz, T. (2024). Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nature Cell Biology. https://doi.org/10.1038/s41556-024-01464-1

MLA:

Schwab, Annemarie, et al. "Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition." Nature Cell Biology (2024).

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