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Oncogenic Hedgehog-Smoothened Signaling Depends on YAP1‒TAZ/TEAD Transcription to Restrain Differentiation in Basal Cell Carcinoma

  • Yao Yuan
    Affiliations
    Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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  • Natalia Salinas Parra
    Affiliations
    Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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  • Qianming Chen
    Affiliations
    The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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  • Ramiro Iglesias-Bartolome
    Correspondence
    Correspondence: Ramiro Iglesias-Bartolome, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892-2590, USA.
    Affiliations
    Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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      Disruption of the transcriptional activity of the Hippo pathway members YAP1 and TAZ has become a major target for cancer treatment. However, detailed analysis of the effectiveness and networks affected by YAP1/TAZ transcriptional targeting is limited. In this study, we utilize TEAD inhibitor, an inhibitor of the binding of YAP1 and TAZ with their main transcriptional target TEAD in a mouse model of basal cell carcinoma, to unveil the consequences of YAP1/TAZ transcriptional blockage in cancer cells. Both TEAD inhibitor and YAP1/TAZ knockdown lead to reduced proliferation and increased differentiation of mouse basal cell carcinoma driven by oncogenic hedgehog-smoothened (SmoM2) activity. Although TEAD-transcriptional networks were essential to inactivate differentiation, this inactivation was found to be indirect and potentially mediated through the repression of KLF4 by SNAI2. By comparing the transcriptional effects of TEAD inhibition with those caused by YAP1/TAZ depletion, we determined YAP1/TAZ‒TEAD‒independent effects in cancer cells that impact STAT3 and NF-κB. Our results reveal the gene networks affected by targeting YAP1/TAZ‒TEAD in basal cell carcinoma tumors and expose the potential pitfalls for targeting TEAD transcription in cancer.

      Graphical abstract

      Abbreviations:

      Ad-TEADi (adenoviruses expressing a GFP-tagged TEAD inhibitor), BCC (basal cell carcinoma), ChIP-seq (chromatin immunoprecipitation sequencing), IPA (ingenuity pathway analysis), K (keratin), KC (keratinocyte), LSL (lox-stop-lox), siYAP1/TAZ (small interfering RNAs targeting YAP1 and TAZ), TEADi (TEAD inhibitor)
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