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Increased genomic instability and altered chromosomal protein phosphorylation timing in HRAS-transformed mouse

Katherine L Dunn1, Shihua He, Landon Wark

  • 1Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0V9.

Genes, Chromosomes & Cancer
|February 5, 2009
PubMed

Insights

RAS-mitogen-activated protein kinase (MAPK) pathway deregulation drives cancer. HRAS-transformed cells show increased genomic instability and altered epigenetic programs, impacting histone modifications and gene transcription.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Epigenetics

Background:

  • The RAS-mitogen-activated protein kinase (MAPK) pathway is frequently dysregulated in cancer.
  • HRAS-transformed mouse fibroblasts (Ciras-3) exhibit constitutive RAS-MAPK activation and increased chromosomal instability compared to parental 10T1/2 cells.

Purpose of the Study:

  • To investigate the impact of HRAS transformation on histone modifications and chromatin structure in response to signaling pathway activation.
  • To explore the relationship between genomic instability, epigenetic alterations, and gene transcription in cancer cells.

Main Methods:

  • Stimulation of cells with phorbol esters (TPA) to induce signaling.
  • Analysis of histone H3 phosphorylation at serine 10 and 28.
  • Assessment of chromatin structure and steady-state levels of phosphorylated H3 and HMGN1.
  • Colocalization studies with RNA polymerase II.
  • Chromatin immunoprecipitation (ChIP) assays to identify gene promoter associations.

Main Results:

  • HRAS-transformed cells displayed delayed TPA-induced histone H3 phosphorylation.
  • These cells showed a more open chromatin structure with increased basal levels of phosphorylated H3 and HMGN1.
  • TPA-induced histone H3 phosphorylation colocalized with active RNA polymerase II and was associated with the JUN promoter, indicating a link to transcription.
  • HRAS transformation led to increased genomic instability and altered epigenetic regulation.

Conclusions:

  • HRAS transformation in fibroblasts results in significant genomic instability and epigenetic reprogramming.
  • Histone modifications, particularly H3 phosphorylation, are altered in timing and basal levels in transformed cells.
  • These epigenetic changes are linked to transcriptional regulation of immediate early genes, contributing to cancer progression.

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