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

The EMBO Journal
Nora FeldkerSimone Brabletz

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.

Associated Datasets

Jul 22, 2020·Thomas BrabletzSimone Brabletz

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Citations

Nov 1, 2020·Cancers·Sophie Mouillet-Richard, Pierre Laurent-Puig
Mar 20, 2021·Seminars in Cancer Biology·Rui ZhangSuling Liu
Jul 2, 2021·Cell Communication and Signaling : CCS·Maria A OrtizLeszek Kotula
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Oct 2, 2021·Proceedings of the National Academy of Sciences of the United States of America·Madhurima Ghosh, Sanjeev Das

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Datasets Mentioned

BETA
GSE66081
GSE18229
GPL1390

Methods Mentioned

BETA
proximity ligation
proximity ligation assay
electrophoretic mobility shift
PCR
transfection
Assay
ChIP

Software Mentioned

KM
ChIPpeakAnno
deeptools
affy
GeneOverlap
bedtools
Enrichr
Leica Application Suite X
cutadapt
limma

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