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A cofactor-induced repressive type of transcription factor condensation can be induced by synthetic peptides to

Yang Tang1, Fan Chen2, Gemin Fang3

  • 1Department of Medical Ultrasound, Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai, 200072, China.

The EMBO Journal
|October 2, 2024
PubMed

Insights

Co-factors like VGLL4 can induce repressive transcriptional factor (TF) condensates, triggering cell death. A peptide mimicking this interaction shows promise for gastric cancer treatment by inhibiting TEAD4-driven gene transcription.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Transcriptional factors (TFs) regulate cell death and survival by controlling gene expression.
  • TEAD4 TFs form condensates in stressed cells, with YAP promoting activation and co-factors like VGLL4 inducing repression.

Purpose of the Study:

  • To investigate the role of co-factors in modulating TEAD4 condensate function.
  • To explore the potential of inducing repressive TEAD4 condensates as an antitumor strategy.

Main Methods:

  • Identification of TFs forming condensates in stressed cells.
  • Analysis of TEAD4-VGLL4 interactions and condensate formation.
  • Engineering of a peptide to induce TEAD4 repressive condensation.
  • Evaluation of the peptide's antitumor effect in gastric cancer mouse models.

Main Results:

  • VGLL4 and RFXANK induce repressive TEAD4 condensates, leading to cell death during glucose starvation.
  • TEAD4-VGLL4 interactions promote large, repressive condensates that entangle DNA and inhibit gene expression.
  • Engineered peptide selectively induces TEAD4 repressive condensation, showing significant antitumor activity in gastric cancer models.

Conclusions:

  • Co-factors can dictate opposing functions of TFs, such as TEAD4's switch between activation and repression.
  • Artificial induction of repressive TF phase separation offers a novel strategy for cancer therapy.
  • The developed peptide demonstrates potential for inhibiting TEAD4-driven transcription in gastric cancer.
Keywords:
CancerGlue PeptideRepressive CondensationTEAD4VGLL Family of Proteins

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