Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth
Open accessAbstract
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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ChIP-seq and deepsequencing studies in cancer and normal cells showed that several YAP-binding regions also show a consensus motif for AP-1 transcriptional factors, suggesting that YAP/TEAD and AP-1 cooperatively regulate target genes.
“ChIP-seq and deepsequencing studies in cancer and normal cells showed that several YAP-binding regions also show a consensus motif for AP-1 transcriptional factors suggesting that YAP/TEAD and AP-1 cooperatively regulate target genes representing a cross-talk between YAP and JNK signalling (74,75).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [75]
The Results section, “Genomic co-occupancy of AP-1 and YAP/TAZ/TEAD,” reports AP-1 motifs in 70% of YAP/TAZ/TEAD peaks and concludes that the factors jointly regulate transcription. However, the ChIP-seq motif findings were obtained in breast cancer cells; the paper’s experiments in non-tumorigenic cells tested growth, not those binding-region motifs. The cited passages also do not establish the citing sentence’s proposed YAP–JNK signaling cross-talk. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA complex consisting of YAP, TAZ, TEADs, and AP-1 synergistically regulates transcription of target genes.
“For instance, a complex consisting of YAP, TAZ, TEADs, and AP-1 (dimer of cFos and transcription factor Jun [JUN] families) was found to synergistically regulate the transcription of target genes (35–37).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [35]
YAP/TEAD bind distal regulatory elements to regulate transcription of target genes.
“Third, YAP/TEAD bind distal regulatory elements to regulate transcription of target genes (73-75).”
From A Tumour-Specific Molecular Network Promotes Tumour Growth in <i>Drosophila</i> by Enforcing a JNK-YKI Feedforward Loop (2023) · cites this paper as [75]
Published ChIP-seq datasets reveal a similar phenomenon in human cancer cell lines.
“Consistently, published ChIP-seq datasets34,38,39 reveal a similar phenomenon in human cancer cell lines (Figure S7F).”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [39]
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References 63 · Cited by 1,219
- Authors
- Zanconato, F., Forcato, M., Battilana, G., Azzolin, L., Quaranta, E., Bodega, B., Rosato, A., Bicciato, S., Cordenonsi, M., & Piccolo, S.
- Affiliations
- University of Padua (IT)
- University of Modena and Reggio Emilia (IT)
- Istituto Nazionale Genetica Molecolare (IT)
- Corresponding author
- Cordenonsi, Michelangelo
- Piccolo, Stefano
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-08-10
- Volume
- 17
- Issue
- 9
- Pages
- 1218-1227
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6186417
- OpenAlex
- W2098692163
- Cited by
- 1,219
- References
- 63
- Citations by year
- 2026: 96 · 2025: 109 · 2024: 126 · 2023: 145 · 2022: 144 · 2021: 119 · 2020: 127 · 2019: 109 · 2018: 107 · 2017: 70 · 2016: 55 · 2015: 8
- FWCI
- 42.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- Johns Hopkins University
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Université de Strasbourg
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- YAP/TAZ, TEAD transcription factors, AP-1, Fos/Jun, Hippo signaling pathway, transcriptional regulation, enhancers, chromatin looping, S phase entry, mitosis, skin carcinogenesis, breast cancer cells, conditional knockout mice
- MeSH terms
- YAP-Signaling Proteins, TEA Domain Transcription Factors, Acyltransferases, Animals, DNA-Binding Proteins, Enhancer Elements, Genetic, Female, Humans, Male, Nuclear Proteins, Phosphoproteins, Protein Binding, Skin Neoplasms, Transcription Factors, Signal Transduction, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Mice, Knockout, Transcription Factor AP-1, Cell Line, Tumor, Tumor Burden, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, HEK293 Cells, Carcinogenesis
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