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Genome‐wide cooperation of EMT transcription factor ZEB 1 with YAP and AP ‐1 in breast cancer
Author(s) -
Feldker Nora,
Ferrazzi Fulvia,
Schuhwerk Harald,
Widholz Sebastian A,
Guenther Kerstin,
Frisch Isabell,
Jakob Kathrin,
Kleemann Julia,
Riegel Dania,
Bönisch Ulrike,
Lukassen Sören,
Eccles Rebecca L,
Schmidl Christian,
Stemmler Marc P,
Brabletz Thomas,
Brabletz Simone
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103209
Subject(s) - biology , transcription factor , breast cancer , microbiology and biotechnology , dna binding protein , transcription (linguistics) , genome , genetics , gene , cancer , linguistics , philosophy
Invasion, metastasis and therapy resistance are the major cause of cancer‐associated deaths, and the EMT ‐inducing transcription factor ZEB 1 is a crucial stimulator of these processes. While work on ZEB 1 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 ZEB 1 binding study in triple‐negative breast cancer cells. We identified ZEB 1 as a novel interactor of the AP ‐1 factors FOSL 1 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 ZEB 1, YAP , FOSL 1 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: ZEB 1, AP ‐1 and Hippo pathway factors. Disturbing their molecular interaction may provide a promising treatment option for aggressive cancer types.