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

doi:10.1093/nar/gku281

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

Nucleic Acids Res. 2014 Jun;42(10):6256-69. doi: 10.1093/nar/gku281. Epub 2014 Apr 21.

Authors

Affiliations

¹ Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Department of Urology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
² Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
³ Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany.
⁴ Department of Bioinformatics, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
⁵ Department of Pathology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
⁶ Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Department of Urology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK den22@medschl.cam.ac.uk.
⁷ Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Gaustadalleen 21, Oslo N-0349, Norway Department of Cancer Prevention and Department of Urology, Oslo University Hospital, Oslo N-0349, Norway.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

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

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Abstract

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