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Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens

Author

Listed:
  • Inês A. M. Barbosa

    (Novartis Institutes for Biomedical Research)

  • Rajaraman Gopalakrishnan

    (Novartis Institutes for Biomedical Research
    Alltrna Inc., One Kendall Square)

  • Samuele Mercan

    (Novartis Institutes for Biomedical Research)

  • Thanos P. Mourikis

    (Novartis Institutes for Biomedical Research)

  • Typhaine Martin

    (Novartis Institutes for Biomedical Research)

  • Simon Wengert

    (Novartis Institutes for Biomedical Research
    Helmholtz Zentrum München GmbH German Research Center for Environmental Health)

  • Caibin Sheng

    (Novartis Institutes for Biomedical Research)

  • Fei Ji

    (Novartis Institutes for Biomedical Research)

  • Rui Lopes

    (Novartis Institutes for Biomedical Research
    Roche Pharmaceutical Research and Early Development)

  • Judith Knehr

    (Novartis Institutes for Biomedical Research)

  • Marc Altorfer

    (Novartis Institutes for Biomedical Research)

  • Alicia Lindeman

    (Novartis Institutes for Biomedical Research)

  • Carsten Russ

    (Novartis Institutes for Biomedical Research)

  • Ulrike Naumann

    (Novartis Institutes for Biomedical Research)

  • Javad Golji

    (Novartis Institutes for Biomedical Research)

  • Kathleen Sprouffske

    (Novartis Institutes for Biomedical Research)

  • Louise Barys

    (Novartis Institutes for Biomedical Research)

  • Luca Tordella

    (Novartis Institutes for Biomedical Research)

  • Dirk Schübeler

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Tobias Schmelzle

    (Novartis Institutes for Biomedical Research)

  • Giorgio G. Galli

    (Novartis Institutes for Biomedical Research)

Abstract

YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.

Suggested Citation

  • Inês A. M. Barbosa & Rajaraman Gopalakrishnan & Samuele Mercan & Thanos P. Mourikis & Typhaine Martin & Simon Wengert & Caibin Sheng & Fei Ji & Rui Lopes & Judith Knehr & Marc Altorfer & Alicia Lindem, 2023. "Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39527-w
    DOI: 10.1038/s41467-023-39527-w
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    1. Matthew C. Canver & Elenoe C. Smith & Falak Sher & Luca Pinello & Neville E. Sanjana & Ophir Shalem & Diane D. Chen & Patrick G. Schupp & Divya S. Vinjamur & Sara P. Garcia & Sidinh Luc & Ryo Kurita &, 2015. "BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis," Nature, Nature, vol. 527(7577), pages 192-197, November.
    2. Catherine D. Van Raamsdonk & Vladimir Bezrookove & Gary Green & Jürgen Bauer & Lona Gaugler & Joan M. O’Brien & Elizabeth M. Simpson & Gregory S. Barsh & Boris C. Bastian, 2009. "Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi," Nature, Nature, vol. 457(7229), pages 599-602, January.
    3. Drew T. Bergman & Thouis R. Jones & Vincent Liu & Judhajeet Ray & Evelyn Jagoda & Layla Siraj & Helen Y. Kang & Joseph Nasser & Michael Kane & Antonio Rios & Tung H. Nguyen & Sharon R. Grossman & Char, 2022. "Compatibility rules of human enhancer and promoter sequences," Nature, Nature, vol. 607(7917), pages 176-184, July.
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