A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer

Cancer Cell. 2014 Feb 10;25(2):166-80. doi: 10.1016/j.ccr.2014.01.010.

Abstract

The Hippo pathway has been implicated in suppressing tissue overgrowth and tumor formation by restricting the oncogenic activity of YAP. However, transcriptional regulators that inhibit YAP activity have not been well studied. Here, we uncover clinical importance for VGLL4 in gastric cancer suppression and find that VGLL4 directly competes with YAP for binding TEADs. Importantly, VGLL4's tandem Tondu domains are not only essential but also sufficient for its inhibitory activity toward YAP. A peptide mimicking this function of VGLL4 potently suppressed tumor growth in vitro and in vivo. These findings suggest that disruption of YAP-TEADs interaction by a VGLL4-mimicking peptide may be a promising therapeutic strategy against YAP-driven human cancers.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Case-Control Studies
  • Cell Cycle Proteins
  • Cell Survival
  • DNA-Binding Proteins / metabolism*
  • Female
  • Fluorouracil / pharmacology
  • Gastric Mucosa / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Middle Aged
  • Molecular Mimicry*
  • Muscle Proteins / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Peptide Fragments / pharmacology*
  • Protein Conformation
  • Stomach / pathology
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / prevention & control*
  • Tissue Array Analysis
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Antimetabolites, Antineoplastic
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Muscle Proteins
  • Nuclear Proteins
  • Peptide Fragments
  • TEAD4 protein, human
  • Transcription Factors
  • VGLL4 protein, human
  • YY1AP1 protein, human
  • Fluorouracil