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

Chi Zhu, Li Li, Zhao Zhang, Mingjun Bi, Hu Wang, Wenyue Su, Karen Hernandez, Pingping Liu, Junqiang Chen, Mingqiu Chen, Tim Hui Ming Huang, Lizhen Chen, Zhijie Liu

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3 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)791-806.e8
JournalMolecular Cell
Volume75
Issue number4
DOIs
StatePublished - Aug 22 2019

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Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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