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The oncogenic axis YAP/MYC/EZH2 impairs PTEN tumor suppression activity enhancing lung tumorigenicity

Federica Lo Sardo1, Chiara Turco1, Beatrice Messina2

  • 1Translational Oncology Research Unit, Department of Research, Diagnosis and Innovative Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Cell Death Discovery
|October 25, 2024
PubMed

Insights

The YAP/TAZ-EZH2-MYC complex represses PTEN tumor suppressor in lung cancer. Targeting this axis restores PTEN, reduces cancer growth, and improves prognosis for patients with low PTEN levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Tumor suppressor PTEN (phosphatase and tensin homolog deleted in chromosome 10) loss is common in cancers, particularly lung cancer.
  • PTEN downregulation, often without genetic alteration, increases cancer risk.
  • PTEN expression is tightly regulated by genetic and epigenetic factors.

Purpose of the Study:

  • To investigate the molecular mechanisms regulating PTEN expression in non-small cell lung cancer (NSCLC).
  • To identify key regulators that repress PTEN and explore therapeutic strategies targeting this pathway.

Main Methods:

  • Utilized molecular biology techniques to study gene regulation in NSCLC cells.
  • Analyzed patient datasets to correlate PTEN expression with clinical outcomes and molecular markers.
  • Investigated the formation and function of a nuclear complex involving YAP, TAZ, EZH2, and MYC.

Main Results:

  • YAP, TAZ, EZH2, and MYC form a complex that transcriptionally represses PTEN in NSCLC.
  • Combinatorial targeting of this YAP/TAZ-EZH2-MYC axis restores PTEN expression and inhibits NSCLC cell growth.
  • Low PTEN expression in NSCLC patients correlates with higher YAP/TAZ, EZH2, and MYC levels and predicts poor prognosis.

Conclusions:

  • The YAP/TAZ-EZH2-MYC axis plays a critical role in suppressing PTEN in NSCLC.
  • Targeting this axis represents a promising therapeutic strategy for NSCLC patients with reduced PTEN expression.
  • Restoring PTEN levels offers a potential pathway to improve treatment outcomes in lung cancer.

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