Abstract
Invasion, metastasis and therapy resistance are the major cause of cancer-associated deaths, and theEMT-inducing transcription factorZEB1 is a crucial stimulator of these processes. While work onZEB1 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-wideZEB1 binding ...
Abstract
Invasion, metastasis and therapy resistance are the major cause of cancer-associated deaths, and theEMT-inducing transcription factorZEB1 is a crucial stimulator of these processes. While work onZEB1 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-wideZEB1 binding study in triple-negative breast cancer cells. We identifiedZEB1 as a novel interactor of theAP-1 factorsFOSL1 andJUNand show that, together with the Hippo pathway effectorYAP, they form a transactivation complex, predominantly activating tumour-promoting genes, thereby synergising with its function as a repressor of epithelial genes. High expression ofZEB1,YAP,FOSL1 andJUNmarks 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.