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Barbosa, I.A.M.* ; Gopalakrishnan, R.* ; Mercan, S.* ; Mourikis, T.P.* ; Martin, T.* ; Wengert, S. ; Sheng, C.* ; Ji, F.* ; Lopes, R.* ; Knehr, J.* ; Altorfer, M.* ; Lindeman, A.* ; Russ, C.* ; Naumann, U.* ; Golji, J.* ; Sprouffske, K.* ; Barys, L.* ; Tordella, L.* ; Schübeler, D.* ; Schmelzle, T.* ; Galli, G.G.*

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

Nat. Commun. 14:3907 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Hippo Signaling Pathway; Uveal Melanoma; Size-control; Organ Size; Mutations; Activation; Induction; Biology; Growth; Ap-1

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 14, Issue: 1, Article Number: 3907

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Pioneer Campus (HPC)

Grants Swiss National Science Foundation (SNF)
European Research Council
Swiss National Science Foundation
Novartis Research Foundation