Targeting IRF3 as a YAP agonist therapy against gastric cancer

• Published in: The Journal of experimental medicine 2018-02, Vol.215 (2), p.699-718
• Main Authors: Jiao, Shi, Guan, Jingmin, Chen, Min, Wang, Wenjia, Li, Chuanchuan, Wang, Yugong, Cheng, Yunfeng, Zhou, Zhaocai
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - agonists; Aminopyridines - chemistry; Aminopyridines - pharmacology; Animals; Cancer; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; DNA-Binding Proteins - metabolism; Female; Gastric cancer; Gene expression; Genes; Genome-Wide Association Study; Genomes; HEK293 Cells; Homeostasis; Humans; Immunity; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - metabolism; Male; Mice, Inbred C57BL; Middle Aged; Molecular Targeted Therapy; Muscle Proteins - metabolism; Nuclear transport; Pharmacology; Phosphoproteins - agonists; Protein Binding; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Therapeutic targets; Transcription Factors - metabolism; Translocation; Tumorigenesis; Viruses - metabolism; Yes-associated protein
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20171116

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.