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Pharmacological research

Pharmacological research

IF: 9.1
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Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors

Published:1 October 2022 DOI: 10.1016/j.phrs.2022.106464 PMID: 36162600
Gui-Ming Zhang , Si-Si Huang , Lin-Xuan Ye , Xiao-Lian Liu , Wen-Hui Shi , Zhong-Lu Ren , Run-Hua Zhou , Jia-Jie Zhang , Jing-Xuan Pan , Shu-Wen Liu , Le Yu , Yi-Lei Li

Abstract

Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.

Substances (60)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Triptolide 38748-32-2 C20H24O6 533 suppliers $25.00-$4741.00
Triptolide 38748-32-2 C20H24O6 533 suppliers $25.00-$4741.00
Triptolide 38748-32-2 C20H24O6 533 suppliers $25.00-$4741.00
Triptolide 38748-32-2 C20H24O6 533 suppliers $25.00-$4741.00
Selumetinib 606143-52-6 C17H15BrClFN4O3 374 suppliers $10.00-$3538.00
Selumetinib 606143-52-6 C17H15BrClFN4O3 374 suppliers $10.00-$3538.00
Selumetinib 606143-52-6 C17H15BrClFN4O3 374 suppliers $10.00-$3538.00
Selumetinib 606143-52-6 C17H15BrClFN4O3 374 suppliers $10.00-$3538.00
(+)-JQ-1 1268524-70-4 C23H25ClN4O2S 294 suppliers $9.00-$5000.00
(+)-JQ-1 1268524-70-4 C23H25ClN4O2S 294 suppliers $9.00-$5000.00

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