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 E stimulation and is required for the induction of E/ERα target genes and E-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 ME... More
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 E stimulation and is required for the induction of E/ERα target genes and E-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.
