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

ABSTRACT: 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 ER? on enhancers. The binding of YAP1/TEAD4 to ER?-bound enhancers is augmented upon E2 stimulation and is required for the induction of E2/ER? 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 ER? cofactors in regulating cancer growth, highlighting the potential of YAP/TEAD as possible actionable drug targets for ER?+ breast cancer.

SUBMITTER: Zhu C 

PROVIDER: S-EPMC6707877 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature