TMPRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation

Oncogene. 2015 Jul;34(29):3815-25. doi: 10.1038/onc.2014.308. Epub 2014 Sep 29.

Abstract

The biological outcome of TMPRSS2:ERG chromosomal translocations in prostate cancer (PC) remains poorly understood. To address this, we compared the transcriptional effects of TMPRSS2:ERG expression in a transgenic mouse model with those of ERG knockdown in a TMPRSS2:ERG-positive PC cell line. This reveals that ERG represses the expression of a previously unreported set of androgen receptor (AR)-independent neuronal genes that are indicative of neuroendocrine (NE) cell differentiation-in addition to previously reported AR-regulated luminal genes. Cell sorting and proliferation assays performed after sustained ERG knockdown indicate that ERG drives proliferation and blocks the differentiation of prostate cells to both NE and luminal cell types. Inhibition of ERG expression in TMPRSS2:ERG-positive PC cells through blockade of AR signaling is tracked with increased NE gene expression. We also provide evidence that these NE cells are resistant to pharmacological AR inhibition and can revert to the phenotype of parental cells upon restoration of AR/ERG signaling. Our findings highlight an ERG-regulated mechanism capable of repopulating the parent tumor through the transient generation of an anti-androgen therapy-resistant cell population, suggesting that ERG may have a direct role in preventing resistance to anti-androgen therapy.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Benzamides
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics*
  • Disease Models, Animal
  • Doxorubicin / pharmacology
  • Epithelial Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry
  • Male
  • Mice, Transgenic
  • Microscopy, Confocal
  • Neuroendocrine Cells / metabolism
  • Nitriles
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • RNA Interference
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcriptional Regulator ERG
  • Translocation, Genetic

Substances

  • Antibiotics, Antineoplastic
  • Benzamides
  • ERG protein, human
  • Nitriles
  • Oncogene Proteins, Fusion
  • Receptors, Androgen
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Phenylthiohydantoin
  • Doxorubicin
  • enzalutamide
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Associated data

  • GEO/GSE60771
  • GEO/GSE61008