Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells

PLoS Genet. 2021 Jul 27;17(7):e1009708. doi: 10.1371/journal.pgen.1009708. eCollection 2021 Jul.

Abstract

The TMPRSS2/ERG gene rearrangement occurs in 50% of prostate tumors and results in expression of the transcription factor ERG, which is normally silent in prostate cells. ERG expression promotes prostate tumor formation and luminal epithelial cell fates when combined with PI3K/AKT pathway activation, however the mechanism of synergy is not known. In contrast to luminal fates, expression of ERG alone in immortalized normal prostate epithelial cells promotes cell migration and epithelial to mesenchymal transition (EMT). Migration requires ERG serine 96 phosphorylation via endogenous Ras/ERK signaling. We found that a phosphomimetic mutant, S96E ERG, drove tumor formation and clonogenic survival without activated AKT. S96 was only phosphorylated on nuclear ERG, and differential recruitment of ERK to a subset of ERG-bound chromatin associated with ERG-activated, but not ERG-repressed genes. S96E did not alter ERG genomic binding, but caused a loss of ERG-mediated repression, EZH2 binding and H3K27 methylation. In contrast, AKT activation altered the ERG cistrome and promoted expression of luminal cell fate genes. These data suggest that, depending on AKT status, ERG can promote either luminal or EMT transcription programs, but ERG can promote tumorigenesis independent of these cell fates and tumorigenesis requires only the transcriptional activation function.

Publication types

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

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Transformation, Neoplastic / genetics
  • Epithelial-Mesenchymal Transition
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Expression Regulation, Neoplastic / physiology
  • Genes, Regulator
  • Heterografts
  • Humans
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / genetics
  • Prostate / pathology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcriptional Activation
  • Transcriptional Regulator ERG / genetics
  • Transcriptional Regulator ERG / metabolism
  • ras Proteins / metabolism

Substances

  • ERG protein, human
  • Transcription Factors
  • Transcriptional Regulator ERG
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins