The Tumor Suppressor Interferon Regulatory Factor 2 Binding Protein 2 Regulates Hippo Pathway in Liver Cancer by a Feedback Loop in Mice.
Animals
Carcinogenesis
/ metabolism
Cell Proliferation
DNA-Binding Proteins
/ metabolism
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Hippo Signaling Pathway
Liver Neoplasms
/ metabolism
Mice
Muscle Proteins
/ metabolism
Protein Serine-Threonine Kinases
/ metabolism
Signal Transduction
TEA Domain Transcription Factors
Transcription Factors
/ metabolism
Tumor Suppressor Proteins
/ metabolism
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
24
04
2019
accepted:
14
09
2019
pubmed:
21
9
2019
medline:
29
4
2021
entrez:
21
9
2019
Statut:
ppublish
Résumé
The conserved Hippo pathway regulates organ size, tissue homeostasis, and tumorigenesis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) was originally identified as a transcriptional corepressor. However, the association between IRF2BP2 and the Hippo pathway remains largely unknown. In addition, the biological function and regulation mechanism of IRF2BP2 in liver cancer are poorly understood. In this study, we uncovered the clinical significance of IRF2BP2 in suppressing hepatocellular carcinogenesis. We showed that IRF2BP2, a direct target repressed by the Yes-associated protein (YAP)/TEA domain transcription factor 4 (TEAD4) transcriptional complex, inhibited YAP activity through a feedback loop. IRF2BP2 stabilized vestigial-like family member 4 (VGLL4) and further enhanced VGLL4's inhibitory function on YAP. Moreover, liver-specific IRF2BP2 overexpression suppressed tumor formation induced by Hippo pathway inactivation. These results revealed the important role of IRF2BP2 in repressing liver cancer progression and highlighted a feedback loop underlying the Hippo pathway in organ-size control and tumorigenesis.
Sections du résumé
BACKGROUND AND AIMS
The conserved Hippo pathway regulates organ size, tissue homeostasis, and tumorigenesis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) was originally identified as a transcriptional corepressor. However, the association between IRF2BP2 and the Hippo pathway remains largely unknown. In addition, the biological function and regulation mechanism of IRF2BP2 in liver cancer are poorly understood.
APPROACH AND RESULTS
In this study, we uncovered the clinical significance of IRF2BP2 in suppressing hepatocellular carcinogenesis. We showed that IRF2BP2, a direct target repressed by the Yes-associated protein (YAP)/TEA domain transcription factor 4 (TEAD4) transcriptional complex, inhibited YAP activity through a feedback loop. IRF2BP2 stabilized vestigial-like family member 4 (VGLL4) and further enhanced VGLL4's inhibitory function on YAP. Moreover, liver-specific IRF2BP2 overexpression suppressed tumor formation induced by Hippo pathway inactivation.
CONCLUSIONS
These results revealed the important role of IRF2BP2 in repressing liver cancer progression and highlighted a feedback loop underlying the Hippo pathway in organ-size control and tumorigenesis.
Substances chimiques
DNA-Binding Proteins
0
IRF2BP2 protein, mouse
0
Muscle Proteins
0
TEA Domain Transcription Factors
0
Tead4 protein, mouse
0
Transcription Factors
0
Tumor Suppressor Proteins
0
VGLL4 protein, mouse
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1988-2004Informations de copyright
© 2019 by the American Association for the Study of Liver Diseases.
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