A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer

• Published in: Molecular cell Vol. 75; no. 4; pp. 791 - 806.e8
• Main Authors: Zhu, Chi, Li, Li, Zhang, Zhao, Bi, Mingjun, Wang, Hu, Su, Wenyue, Hernandez, Karen, Liu, Pingping, Chen, Junqiang, Chen, Mingqiu, Huang, Tim Hui-Ming, Chen, Lizhen, Liu, Zhijie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2019
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; enhancer; Enhancer Elements, Genetic; ERα; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; estrogen signaling; Estrogens - pharmacology; Female; Hippo signaling; Humans; MCF-7 Cells; Mediator Complex Subunit 1 - genetics; Mediator Complex Subunit 1 - metabolism; Mice; Mice, Nude; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; TEA Domain Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - drug effects; transcriptional regulation; YAP-Signaling Proteins; YAP/TEAD; enhancer; Hippo signaling; YAP/TEAD; ERα; transcriptional regulation; estrogen signaling; breast cancer
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.06.010

YAP/TEAD are nuclear effectors of the Hippo pathway, regulating organ size and tumorigenesis largely through promoter-associated function. However, their function as enhancer regulators remains poorly understood. Through an in vivo proximity-dependent labeling (BioID) technique, we identified YAP1 and TEAD4 protein as co-regulators of ERα on enhancers. The binding of YAP1/TEAD4 to ERα-bound enhancers is augmented upon E2 stimulation and is required for the induction of E2/ERα target genes and E2-induced oncogenic cell growth. Furthermore, their enhancer binding is a prerequisite for enhancer activation marked by eRNA transcription and for the recruitment of the enhancer activation machinery component MED1. The binding of TEAD4 on active ERE-containing enhancers is independent of its DNA-binding behavior, and instead, occurs through protein-tethering trans-binding. Our data reveal a non-canonical function of YAP1 and TEAD4 as ERα cofactors in regulating cancer growth, highlighting the potential of YAP/TEAD as possible actionable drug targets for ERα+ breast cancer. [Display omitted] •YAP/TEAD non-canonically bind to a group of ERα-bound enhancers•YAP/TEAD are required for estrogen-induced transcription and breast cancer growth•YAP/TEAD regulate enhancer activation by controlling the recruitment of MED1•TEAD is recruited to ERα active enhancers through protein tethering trans-binding ERα is a key transcription factor that binds to distal enhancers and regulates breast cancer-related gene expression events. Zhu et al. identify the Hippo pathway nuclear effectors YAP/TEAD as ERα cofactors and demonstrate their non-canonical role at the enhancer level to regulate enhancer activation, gene transcription, and breast cancer growth.