論文 - 詳細
| RRC ID | 62053 |
|---|---|
| 著者 | Jiao S, Guan J, Chen M, Wang W, Li C, Wang Y, Cheng Y, Zhou Z. |
| タイトル | Targeting IRF3 as a YAP agonist therapy against gastric cancer. |
| ジャーナル | J Exp Med |
| Abstract |
The Hippo pathway plays a vital role in tissue homeostasis and tumorigenesis. The transcription factor IRF3 is essential for innate antiviral immunity. In this study, we discovered IRF3 as an agonist of Yes-associated protein (YAP). The expression of IRF3 is positively correlated with that of YAP and its target genes in gastric cancer; the expression of both IRF3 and YAP is up-regulated and prognosticates patient survival. IRF3 interacts with both YAP and TEAD4 in the nucleus to enhance their interaction, promoting nuclear translocation and activation of YAP. IRF3 and YAP-TEAD4 are associated genome-wide to cobind and coregulate many target genes of the Hippo pathway. Overexpression of active IRF3 increased, but depletion of IRF3 reduced, the occupancy of YAP on the target genes. Knockdown or pharmacological targeting of IRF3 by Amlexanox, a drug used clinically for antiinflammatory treatment, inhibits gastric tumor growth in a YAP-dependent manner. Collectively, our study identifies IRF3 as a positive regulator for YAP, highlighting a new therapeutic target against YAP-driven cancers. |
| 巻・号 | 215(2) |
| ページ | 699-718 |
| 公開日 | 2018-2-5 |
| DOI | 10.1084/jem.20171116 |
| PII | jem.20171116 |
| PMID | 29339449 |
| PMC | PMC5789414 |
| MeSH | Adaptor Proteins, Signal Transducing / agonists* Aminopyridines / chemistry Aminopyridines / pharmacology Animals Cell Line, Tumor Cell Nucleus / drug effects Cell Nucleus / metabolism Cell Proliferation / drug effects DNA-Binding Proteins / metabolism Female Genome-Wide Association Study HEK293 Cells Humans Interferon Regulatory Factor-3 / genetics Interferon Regulatory Factor-3 / metabolism* Male Mice, Inbred C57BL Middle Aged Molecular Targeted Therapy* Muscle Proteins / metabolism Phosphoproteins / agonists* Protein Binding RNA, Messenger / genetics RNA, Messenger / metabolism Signal Transduction / drug effects Stomach Neoplasms / drug therapy* Stomach Neoplasms / pathology TEA Domain Transcription Factors Transcription Factors / metabolism Viruses / metabolism YAP-Signaling Proteins |
| IF | 11.743 |
| リソース情報 | |
| ヒト・動物細胞 | MKN1(RCB1003) MKN45(RCB1001) |