| Autor: |
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 |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Pharmacological Research. 184:106464 |
| ISSN: |
1043-6618 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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