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

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          Abstract

          YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their working 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 harboring 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 novel layer of signaling integration, feeding on YAP/TAZ function at the chromatin level.

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          Author and article information

          Journal
          100890575
          21417
          Nat Cell Biol
          Nat. Cell Biol.
          Nature cell biology
          1465-7392
          1476-4679
          9 October 2018
          10 August 2015
          September 2015
          14 October 2018
          : 17
          : 9
          : 1218-1227
          Affiliations
          [1 ]Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy
          [2 ]Center for Genome Research, Department of Biomedical Sciences, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy
          [3 ]Genome Biology Unit, Istituto Nazionale di Genetica Molecolare (INGM) 'Romeo and Enrica Invernizzi', via Francesco Sforza 35, Milan 20126, Italy
          [4 ]Department of Surgery, Oncology and Gastroenterology, University of Padua School of Medicine, Via Gattamelata 64, 35126 Padua, Italy
          [5 ]Istituto Oncologico Veneto IRCCS, Via Gattamelata 64, 35126 Padua, Italy
          Author notes
          [* ]To whom correspondence should be addressed. Stefano Piccolo and Michelangelo Cordenonsi, Department of Molecular Medicine, viale Colombo 3, 35100 Padua, Italy, TEL 0039049 8276098, FAX 0039049 8276079, michelangelo.cordenonsi@ 123456unipd.it ; piccolo@ 123456bio.unipd.it
          Article
          PMC6186417 PMC6186417 6186417 ems79986
          10.1038/ncb3216
          6186417
          26258633
          500d0987-ac26-4d08-9066-7c9a210bfb31
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