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

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 Lindeman, Carsten Russ, Ulrike Naumann, Javad Golji, Kathleen Sprouffske, Louise Barys, Luca Tordella, Dirk Schübeler, Tobias Schmelzle and Giorgio G. Galli ()
Additional contact information
Inês A. M. Barbosa: Novartis Institutes for Biomedical Research
Rajaraman Gopalakrishnan: Novartis Institutes for Biomedical Research
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
Caibin Sheng: Novartis Institutes for Biomedical Research
Fei Ji: Novartis Institutes for Biomedical Research
Rui Lopes: Novartis Institutes for Biomedical Research
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
Tobias Schmelzle: Novartis Institutes for Biomedical Research
Giorgio G. Galli: Novartis Institutes for Biomedical Research

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39527-w

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