title: Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth.
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.
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zanconato
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 287 41100 Modena, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Forcato
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Battilana
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Azzolin
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Quaranta
authors.affiliation: Genome Biology Unit, Istituto Nazionale di Genetica Molecolare (INGM) 'Romeo and Enrica Invernizzi', via Francesco Sforza 35 Milan 20126, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bodega
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua School of Medicine, Via Gattamelata 64 35126 Padua, Italy.|Istituto Oncologico Veneto IOV-IRCCS, Via Gattamelata 64 35126 Padua, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 287 41100 Modena, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cordenonsi
authors.affiliation: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3 35126 Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Piccolo
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D011485:Protein Binding; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000091262:TEA Domain Transcription Factors; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D047368:Tumor Burden; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human