The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer

Naomi L Sharma, Charlie E Massie, Falk Butter, Matthias Mann, Helene Bon, Antonio Ramos-Montoya, Suraj Menon, Rory Stark, Alastair D Lamb, Helen E Scott, Anne Y Warren, David E Neal, Ian G Mills

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)
163 Downloads (Pure)

Abstract

In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.

Original languageEnglish
Pages (from-to)6256-69
Number of pages14
JournalNucleic Acids Research
Volume42
Issue number10
Early online date21 Apr 2014
DOIs
Publication statusPublished - 02 Jun 2014

Keywords

  • Androgen Receptor Antagonists
  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • GA-Binding Protein Transcription Factor
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Phenotype
  • Prostatic Neoplasms
  • Receptors, Androgen
  • Signal Transduction
  • Transcription, Genetic

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