Abstract
Early dissemination, metastasis and therapy resistance are central hallmarks of aggressive cancer types and the leading cause of cancer-associated deaths. The EMT-inducing transcriptional repressor ZEB1 is a crucial stimulator of these processes, particularly by coupling the activation of cellular motility with stemness and survival properties. ZEB1 expression is associated with aggressive behaviour in many tumour types, but the potent effects cannot be solely explained by its proven function as a transcriptional repressor of epithelial genes. Here we describe a direct interaction of ZEB1 with the Hippo pathway effector YAP, but notably not with its paralogue TAZ. In consequence, ZEB1 switches its function to a transcriptional co-activator of a ‘common ZEB1/YAP target gene set', thereby linking two pathways with similar cancer promoting effects. This gene set is a predictor of poor survival, therapy resistance and increased metastatic risk in breast cancer, indicating the clinical relevance of our findings.
Highlights
Dissemination, metastasis and therapy resistance are central hallmarks of aggressive cancer types and the leading cause of cancer-associated deaths
It has been demonstrated that the embryonic epithelial– mesenchymal transition (EMT)-program can be activated in cancer cells, which induces an aberrant motility triggering dissemination and metastasis, and confers stemness properties resulting in a migrating cancer stem cells (CSCs)-phenotype[3,4]
ZEB1 expression in these subtypes is correlated with poor survival, therapy resistance and high risk for distant metastasis (Fig. 1b)
Summary
Metastasis and therapy resistance are central hallmarks of aggressive cancer types and the leading cause of cancer-associated deaths. ZEB1 switches its function to a transcriptional co-activator of a ‘common ZEB1/YAP target gene set’, thereby linking two pathways with similar cancer promoting effects This gene set is a predictor of poor survival, therapy resistance and increased metastatic risk in breast cancer, indicating the clinical relevance of our findings. ZEB1 is a transcriptional repressor of epithelial genes, for example, for E-cadherin and cell polarity factors, thereby stimulating an undifferentiated and highly motile phenotype[13] This property of ZEB1 is considered important for metastasis as shown in many model systems[10,14–17]. Functional cooperation of ZEB1 and YAP stimulates the transcriptional activation of a ‘common ZEB1/YAP target gene set’ This gene set is a predictor of poor survival, therapy resistance and increased metastatic risk in hormone receptor-negative breast cancer, indicating the clinical relevance of our findings
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
