Abstract
Concerted co-regulation of multiple signalling pathways is crucial for tissue homoeostasis and tumorigenesis. Here we report that VGLL4, a previously identified YAP antagonist, also functions as a regulator of Wnt/β-catenin signalling. The expression of VGLL4 is significantly downregulated in clinical colorectal carcinoma (CRC) specimens, positively associated with patient survival rate, and inversely correlated with the expression of Wnt target genes in CRCs. Knockdown of VGLL4 enhances proliferation and tumour formation of CRC cells. A designed peptide mimicking the function of VGLL4 effectively inhibits CRC progression in a de novo mouse model. Mechanistically, TEAD4 associates with TCF4 to form a complex and cobind target genes. VGLL4 targets this TEAD4-TCF4 complex to interfere the functional interplay between TEAD4 and TCF4, suppressing the transactivation of TCF4. Collectively, our study indicates that Wnt/β-catenin and Hippo-YAP signalling are directly linked at transcription factor-level, and VGLL4 can target a TEAD4-TCF4 complex to co-regulate both pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics
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Animals
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Cell Line, Tumor
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Cell Proliferation / genetics
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / surgery
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Female
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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HEK293 Cells
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Hippo Signaling Pathway
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Nude
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Mice, Transgenic
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Middle Aged
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Prognosis
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / metabolism
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Survival Rate
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TEA Domain Transcription Factors
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Tissue Array Analysis
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Transcription Factor 4 / genetics
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Transcription Factor 4 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation / genetics
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Wnt Signaling Pathway / genetics*
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Xenograft Model Antitumor Assays
Substances
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Adenomatous Polyposis Coli Protein
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Biomarkers, Tumor
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DNA-Binding Proteins
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Muscle Proteins
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RNA, Small Interfering
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TCF4 protein, human
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TEA Domain Transcription Factors
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TEAD4 protein, human
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Transcription Factor 4
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Transcription Factors
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VGLL4 protein, human
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adenomatous polyposis coli protein, mouse
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Protein Serine-Threonine Kinases