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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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VGLL4 targets a TCF4-TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer

Shi Jiao1, Chuanchuan Li1, Qian Hao1

  • 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Nature Communications
|January 5, 2017
PubMed

Insights

VGLL4, a YAP antagonist, also regulates Wnt/β-catenin signaling. Its downregulation in colorectal cancer (CRC) correlates with poor survival, while VGLL4 peptides inhibit CRC progression by targeting a TEAD4-TCF4 complex.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Co-regulation of signaling pathways is vital for tissue homeostasis and cancer development.
  • VGLL4 is a known YAP antagonist involved in the Hippo pathway.

Purpose of the Study:

  • To investigate the role of VGLL4 in Wnt/β-catenin signaling and colorectal carcinoma (CRC).
  • To elucidate the mechanism by which VGLL4 regulates CRC progression.

Main Methods:

  • Analysis of VGLL4 expression in clinical CRC specimens.
  • CRISPR-Cas9 mediated knockdown of VGLL4 in CRC cells.
  • In vivo studies using a de novo mouse model with a VGLL4-mimicking peptide.
  • Co-immunoprecipitation and chromatin immunoprecipitation assays to study protein-protein and protein-DNA interactions.

Main Results:

  • VGLL4 expression is downregulated in CRC and associated with reduced patient survival.
  • VGLL4 knockdown promotes CRC cell proliferation and tumor formation.
  • A VGLL4-mimicking peptide inhibits CRC progression in mice.
  • VGLL4 disrupts the TEAD4-TCF4 complex, suppressing Wnt/β-catenin target gene transcription.

Conclusions:

  • VGLL4 acts as a tumor suppressor in CRC by co-regulating Hippo-YAP and Wnt/β-catenin pathways.
  • VGLL4 directly links the Hippo-YAP and Wnt/β-catenin signaling pathways at the transcription factor level.
  • Targeting the VGLL4-TEAD4-TCF4 interaction presents a potential therapeutic strategy for CRC.

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