Molecular Cell
Volume 75, Issue 4, 22 August 2019, Pages 791-806.e8
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Article
A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer

https://doi.org/10.1016/j.molcel.2019.06.010Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

enhancer
transcriptional regulation
breast cancer
estrogen signaling
Hippo signaling
YAP/TEAD
ERα

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These authors contributed equally

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