Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth

Nat Cell Biol. 2015 Sep;17(9):1218-27. doi: 10.1038/ncb3216. Epub 2015 Aug 10.

Abstract

YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite cis-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Line, Tumor
  • DNA-Binding Proteins / physiology
  • Enhancer Elements, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genome-Wide Association Study
  • HEK293 Cells
  • Humans
  • Male
  • Mice, Knockout
  • Nuclear Proteins / physiology
  • Phosphoproteins / physiology
  • Protein Binding
  • Signal Transduction
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Transcription Factor AP-1 / genetics*
  • Transcription Factors / physiology
  • Transcriptional Activation*
  • Tumor Burden

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • TAZ protein, human
  • TEAD1 protein, human
  • Transcription Factor AP-1
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human

Associated data

  • GEO/GSE66083