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

F Zanconato, M Forcato, G Battilana, L Azzolin… - Nature cell …, 2015 - nature.com
F Zanconato, M Forcato, G Battilana, L Azzolin, E Quaranta, B Bodega, A Rosato, S Bicciato
Nature cell biology, 2015nature.com
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 …
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.
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