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.
MeSH 主题词
Adaptor Proteins, Signal Transducing/agonists
Aminopyridines/chemistry,pharmacology
Animals
Cell Line, Tumor
Cell Nucleus/drug effects,metabolism
Cell Proliferation/drug effects
DNA-Binding Proteins/metabolism
Female
Genome-Wide Association Study
HEK293 Cells
Humans
Interferon Regulatory Factor-3/genetics,metabolism
Male
Mice, Inbred C57BL
Middle Aged
Molecular Targeted Therapy
Muscle Proteins/metabolism
Phosphoproteins/agonists
Protein Binding
RNA, Messenger/genetics,metabolism
Signal Transduction/drug effects
Stomach Neoplasms/drug therapy,pathology
TEA Domain Transcription Factors
Transcription Factors/metabolism
Viruses/metabolism
YAP-Signaling Proteins
化学物质
Adaptor Proteins, Signal Transducing
Aminopyridines
DNA-Binding Proteins
Interferon Regulatory Factor-3
Muscle Proteins
Phosphoproteins
RNA, Messenger
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
amlexanox
作者与单位
共 8 位作者，点击展开单位 / ORCID
Jiao Shi
ORCID
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
[email protected].
Guan Jingmin
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Chen Min
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Wang Wenjia
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Li Chuanchuan
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Wang Yugong
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. | University of Chinese Academy of Sciences, Beijing, China
Cheng Yunfeng
Department of Hematology and Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
Zhou Zhaocai
ORCID
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. | State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
[email protected]. | University of Chinese Academy of Sciences, Beijing, China
