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

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.