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

Cell Rep. 2015 Aug 25;12(8):1300-13. doi: 10.1016/j.celrep.2015.06.078. Epub 2015 Aug 13.

Abstract

Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRas(G12V) or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, although both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRas(G12V) transformation or Sprouty deletion are largely distinct. Oncogenic HRas(G12V) elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRas(G12V)-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Cell Line
  • Enhancer Elements, Genetic*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GATA4 Transcription Factor / genetics
  • GATA4 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Histones / metabolism
  • MAP Kinase Signaling System*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Kinase C beta / genetics
  • Protein Kinase C beta / metabolism
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • GATA4 Transcription Factor
  • Gata4 protein, mouse
  • Histones
  • Membrane Proteins
  • Phosphoproteins
  • Spry1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Protein Kinase C beta
  • Extracellular Signal-Regulated MAP Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)