Journal Article

ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types

Meisinger, Chris, Mossmann, Dirk, Brummer, Tilman, Kleemann, Julia, Mock, Kerstin, Lehmann, Waltraut, Herr, Ricarda, Brabletz, Simone, Stemmler, Marc P., Brabletz, Thomas

2016

Overview

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. The transcription factors ZEB1 and YAP function in different pathways yet both activate aggressive behaviour in cancer cells. Here, the authors describe that the proteins physically interact and that this changes the transcriptional activity of ZEB1 from a repressor to an activator.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/105 / 13/109 / 13/51 / 13/89 / 14/63 / 38 / 38/15 / 38/77 / 38/90 / 631/67/1347 / 631/80/86 / 82 / 82/29 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Blotting, Western / Breast Neoplasms - metabolism / Cell Line, Tumor / Chromatin Immunoprecipitation / Epithelial-Mesenchymal Transition - genetics / Fluorescent Antibody Technique / Gene Expression Regulation, Neoplastic / HCT116 Cells / HEK293 Cells / Homeodomain Proteins - genetics / Homeodomain Proteins - metabolism / Humanities and Social Sciences / Humans / Immunohistochemistry / Immunoprecipitation / In Vitro Techniques / MCF-7 Cells / multidisciplinary / Phosphoproteins - genetics / Phosphoproteins - metabolism / Reverse Transcriptase Polymerase Chain Reaction / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional Activation - genetics / Zinc Finger E-box-Binding Homeobox 1