Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer

Feldker N, Ferrazzi F, Schuhwerk H, Widholz SA, Guenther K, Frisch I, Jakob K, Kleemann J, Riegel D, Bönisch U, Lukassen S, Eccles R, Schmidl C, Stemmler M, Brabletz T, Brabletz S (2020)

Publication Type: Journal article

Publication year: 2020

Journal

EMBO Journal EMBO Press

DOI: 10.15252/embj.2019103209

Abstract

Invasion, metastasis and therapy resistance are the major cause of cancer-associated deaths, and the EMT-inducing transcription factor ZEB1 is a crucial stimulator of these processes. While work on ZEB1 has mainly focused on its role as a transcriptional repressor, it can also act as a transcriptional activator. To further understand these two modes of action, we performed a genome-wide ZEB1 binding study in triple-negative breast cancer cells. We identified ZEB1 as a novel interactor of the AP-1 factors FOSL1 and JUN and show that, together with the Hippo pathway effector YAP, they form a transactivation complex, predominantly activating tumour-promoting genes, thereby synergising with its function as a repressor of epithelial genes. High expression of ZEB1, YAP, FOSL1 and JUN marks the aggressive claudin-low subtype of breast cancer, indicating the translational relevance of our findings. Thus, our results link critical tumour-promoting transcription factors: ZEB1, AP-1 and Hippo pathway factors. Disturbing their molecular interaction may provide a promising treatment option for aggressive cancer types.

Authors with CRIS profile

Nora Feldker Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Fulvia Ferrazzi Institute of Human Genetics Harald Schuhwerk Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Isabell Armstark Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Kathrin Fuchs Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Julia Kleemann Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Sören Lukassen Professur für Humangenetik Rebecca Eccles Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Marc Stemmler Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Simone Brabletz Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung)

Involved external institutions

Universitätsklinikum Regensburg DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics DE Germany (DE)

How to cite

APA:

Feldker, N., Ferrazzi, F., Schuhwerk, H., Widholz, S.A., Guenther, K., Frisch, I.,... Brabletz, S. (2020). Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer. EMBO Journal. https://doi.org/10.15252/embj.2019103209

MLA:

Feldker, Nora, et al. "Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer." EMBO Journal (2020).

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