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Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in

Michela Serresi1, Gaetano Gargiulo1, Natalie Proost1

  • 1Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.

Cancer Cell
|January 15, 2016
PubMed

Insights

Polycomb repressive complex 2 (PRC2) critically regulates KRAS-driven lung cancer. Its inactivation alters tumor progression and chromatin states, with implications for cancer therapy.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Lung Cancer Research

Background:

  • Polycomb repressive complexes (PRC) play dual roles in cancer, acting as oncogenes or tumor suppressors.
  • KRAS mutations are common drivers in non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To investigate the role of PRC2 in the progression of KRAS-driven NSCLC.
  • To explore the impact of PRC2 modulation on tumor development and phenotype.

Main Methods:

  • Utilized mouse models with specific genetic alterations (Ezh2 overexpression, Eed deletion, Trp53 inactivation).
  • Analyzed epigenetic changes (histone methylation/acetylation) and gene expression.
  • Examined tumor phenotypes, inflammation, and cell-autonomous programs.

Main Results:

  • PRC2 modulation (Ezh2 overexpression or Eed deletion) impacts KRAS-driven lung tumorigenesis and inflammation.
  • Eed loss promotes inflammation, macrophage recruitment, and tissue dysfunction.
  • Trp53 inactivation combined with Eed loss induces epithelial-to-mesenchymal transition and invasive adenocarcinoma.
  • Tumor evolution involves chromatin state switching and altered Hippo/Wnt signaling.

Conclusions:

  • PRC2 is a critical regulator of KRAS-driven NSCLC progression, influencing tumor phenotype through epigenetic mechanisms.
  • PRC2 inactivation leads to context-dependent alterations with potential therapeutic implications.
  • Findings in mouse models are conserved in human cells, highlighting translational relevance.

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