Abstract
Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the βTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Protein-alpha / metabolism*
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Calcium-Calmodulin-Dependent Protein Kinases
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Cycle Proteins
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Cell Differentiation
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Cell Proliferation
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Liver Neoplasms / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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T Cell Transcription Factor 1 / genetics
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T Cell Transcription Factor 1 / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Biomarkers, Tumor
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CCAAT-Enhancer-Binding Protein-alpha
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Cell Cycle Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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RNA, Messenger
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T Cell Transcription Factor 1
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TCF7 protein, human
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Transcription Factors
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Wnt Proteins
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YY1AP1 protein, human
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beta Catenin
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Calcium-Calmodulin-Dependent Protein Kinases
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TRIB2 protein, human
Associated data
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GEO/GSE46465
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GEO/GSE46466