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

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

Author information

  • 1Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
  • 2Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 287 41100 Modena, Italy.
  • 3Genome Biology Unit, Istituto Nazionale di Genetica Molecolare (INGM) 'Romeo and Enrica Invernizzi', via Francesco Sforza 35 Milan 20126, Italy.
  • 4Department of Surgery, Oncology and Gastroenterology, University of Padua School of Medicine, Via Gattamelata 64 35126 Padua, Italy.
  • 5Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64 35126 Padua, Italy.

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.

PMID:
26258633
[PubMed - indexed for MEDLINE]
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