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Updated: Sep 4, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and

Bo-Kuan Wu1, Szu-Chieh Mei2, Elizabeth H Chen2

  • 1Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature Genetics
|July 14, 2022
PubMed

Insights

Oncoprotein YAP activates TET1, a DNA demethylase, to reprogram epigenetics and drive liver cancer. Inhibiting TET1 reverses these changes and suppresses tumor growth, highlighting TET1 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Epigenetic alterations are crucial for cancer development.
  • The role of DNA methylation reprogramming by oncogenic signaling is not fully understood.
  • YAP oncoprotein is frequently activated in human cancers.

Purpose of the Study:

  • To investigate how YAP signaling influences DNA methylation.
  • To identify regulators of YAP-mediated epigenetic reprogramming.
  • To explore TET1 as a potential therapeutic target in YAP-driven cancers.

Main Methods:

  • Yeast-three-hybrid screening
  • ChIP-sequencing
  • RNA-sequencing
  • Demethylation assays
  • Tumorigenesis studies in mice

Main Results:

  • TET1 is a direct YAP target gene, upregulated by YAP activation.
  • YAP-TET1 interaction drives DNA demethylation, H3K27 acetylation, and chromatin opening at YAP target genes.
  • TET1 depletion reverses YAP-induced epigenetic changes and suppresses liver cancer progression.
  • TET1 is essential for YAP-mediated hepatomegaly and tumorigenesis.

Conclusions:

  • YAP signaling utilizes TET1 to orchestrate genome-wide epigenetic reprogramming.
  • TET1-mediated DNA demethylation is a key mechanism in YAP-driven tumorigenesis.
  • Targeting TET1 could be a strategy to counteract YAP signaling in cancer therapy.

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