Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth
By F. Zanconato, M. Forcato, G. Battilana, L. Azzolin, E. Quaranta, B. Bodega, Antonio Rosato, S. Bicciato, M. Cordenonsi, S. Piccolo. Nature Cell Biology, 2015
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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.
Subfields: Cell Biology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/ca6d5f3a5528f59b02ad18c808c07019bcfa7424
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Citations in the corpus
- Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “…a TEAD/YAP/AP 1 ternary complex to regulate activity of distal enhancers, whereas ZEB 1 and YAP are part of a multimeric complex with AP 1 factors independent of direct ZEB 1 DNA binding to drive gene expression on a genome-wide level (Zanconato et al , 2015 ; Feldker et al , 2020 ) (Fig 4 B).”
- Integrin-mediated mechanotransduction (2016, background): “…of the effects of ECM stiffness on cell proliferation and differentiation can be attributed to YAP and TAZ (YAP/ TAZ), two transcriptional activators that operate in the Hippo pathway to induce the expression of prosurvival genes (Dupont et al., 2011; Aragona et al., 2013; Zanconato et al., 2015).”
- Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance (2019, background): “Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth.”
- YAP/TAZ at the roots of cancer (2016, background): “Notably, YAP/TAZ may indirectly reinforce their control over the cell cycle by inducing other proto-oncogenic transcription factors, such as c-Myc (Zanconato et al., 2015).”
- Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “In addition, the majority of YAP and TEAD occupied sites in the genome are shared (Stein et al., 2015; Zanconato et al., 2015; Zhao et al., 2008), and when TEAD is fused with a VP16”
- The Hippo Signaling Pathway in Development and Disease (2019, background): “profiling and chromatin immunoprecipitation analysis confirmed that genes related to cell proliferation and cell death are enriched among all Hippo target genes in both Drosophila and mammals (Kapoor et al., 2014; Oh et al., 2013; Zanconato et al., 2015).”