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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape

Behnam Nabet1, Pilib Ó Broin2, Jaime M Reyes3

  • 1Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Cell Reports
|August 18, 2015
PubMed

Insights

Oncogenic receptor tyrosine kinase (RTK) signaling alters enhancer landscapes by changing histone modifications. This reprogramming impacts gene expression and cell transformation, revealing a key mechanism in tumorigenesis.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Unrestrained receptor tyrosine kinase (RTK) signaling drives tumorigenesis.
  • Epigenetic deregulation is a critical factor in cancer development.
  • The interplay between RTK signaling and epigenetic modifications remains an active area of research.

Purpose of the Study:

  • To investigate the link between aberrant RTK signaling and epigenetic changes.
  • To understand how oncogenic HRas(G12V) or Sprouty gene deletion impacts enhancer landscapes.
  • To identify key transcription factors and signaling pathways involved in RTK-driven epigenetic reprogramming.

Main Methods:

  • Utilized models of oncogenic HRas(G12V) expression and Sprouty gene deletion.
  • Analyzed histone modifications, specifically histone 3 lysine 27 acetylation (H3K27ac), at enhancers.
  • Assessed gene expression profiles and transcription factor networks.
  • Performed functional studies using Gata4 and Prkcb knockdown.

Main Results:

  • Aberrant RTK signaling remodels histone modifications at active enhancers.
  • HRas(G12V) transformation and Sprouty deletion distinctively alter expression programs and enhancer signatures.
  • Oncogenic HRas(G12V) increases H3K27ac levels and expression of Gata4 and Prkcb.
  • Gata4 is essential for aberrant gene expression and H3K27ac marking; Prkcb is required for HRas(G12V) oncogenic effects.

Conclusions:

  • Dynamic reprogramming of the cellular enhancer landscape is a significant consequence of oncogenic RTK signaling.
  • Specific transcription factors and signaling molecules mediate the effects of RTK activation on epigenetic modifications.
  • Findings highlight the importance of enhancer regulation in RTK-driven tumorigenesis.

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