TEA Domain Transcription Factor 4 Is the Major Mediator of Yes-Associated Protein Oncogenic Activity in Mouse and Human Hepatoblastoma.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Carcinoma, Hepatocellular
/ genetics
Cell Proliferation
DNA-Binding Proteins
/ genetics
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms
/ genetics
Lung Neoplasms
/ genetics
Male
Mice
Muscle Proteins
/ genetics
Prognosis
TEA Domain Transcription Factors
Transcription Factors
/ genetics
Tumor Cells, Cultured
YAP-Signaling Proteins
Journal
The American journal of pathology
ISSN: 1525-2191
Titre abrégé: Am J Pathol
Pays: United States
ID NLM: 0370502
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
14
09
2018
revised:
16
01
2019
accepted:
24
01
2019
pubmed:
23
2
2019
medline:
12
2
2020
entrez:
23
2
2019
Statut:
ppublish
Résumé
Hepatoblastoma (HB) is the most common type of pediatric liver cancer. Activation of yes-associated protein (YAP) has been implicated in HB molecular pathogenesis. The transcriptional co-activator Yap regulates downstream gene expression through interaction with the TEA domain (TEAD) proteins. Nonetheless, YAP also displays functions that are independent of its transcriptional activity. The underlying molecular mechanisms by which Yap promotes HB development remain elusive. In the current study, we demonstrated that blocking TEAD function via the dominant-negative form of TEAD2 abolishes Yap-driven HB formation in mice and restrains human HB growth in vitro. When TEAD2 DNA-binding domain was fused with virus protein 16 transcriptional activation domain, it synergized with activated β-catenin to promote HB formation in vivo. Among TEAD genes, silencing of TEAD4 consistently inhibited tumor growth and Yap target gene expression in HB cell lines. Furthermore, TEAD4 mRNA expression was significantly higher in human HB lesions when compared with corresponding nontumorous liver tissues. Human HB specimens also exhibited strong nuclear immunoreactivity for TEAD4. Altogether, data demonstrate that TEAD-mediated transcriptional activity is both sufficient and necessary for Yap-driven HB development. TEAD4 is the major TEAD isoform and Yap partner in human HB. Targeting TEAD4 may represent an effective treatment option for human HB.
Identifiants
pubmed: 30794805
pii: S0002-9440(18)30776-4
doi: 10.1016/j.ajpath.2019.01.016
pmc: PMC6526503
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Biomarkers, Tumor
0
DNA-Binding Proteins
0
Muscle Proteins
0
TEA Domain Transcription Factors
0
TEAD4 protein, human
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1077-1090Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136606
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204586
Pays : United States
Informations de copyright
Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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