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

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 synergizing 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.