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

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

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	6256-69
Number of pages	14
Journal	Nucleic Acids Research
Volume	42
Issue number	10
Early online date	21 Apr 2014
DOIs	https://doi.org/10.1093/nar/gku281
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/nar/gku281

The ETS family member GABP modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer
© The Author(s) 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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Sharma, N. L., Massie, C. E., Butter, F., Mann, M., Bon, H., Ramos-Montoya, A., Menon, S., Stark, R., Lamb, A. D., Scott, H. E., Warren, A. Y., Neal, D. E., & Mills, I. G. (2014). The ETS family member GABPα modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer. Nucleic Acids Research, 42(10), 6256-69. https://doi.org/10.1093/nar/gku281

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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.",

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AB - 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.

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KW - Animals

KW - Cell Line, Tumor

KW - Drug Resistance, Neoplasm

KW - GA-Binding Protein Transcription Factor

KW - Gene Expression Regulation, Neoplastic

KW - Gene Regulatory Networks

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Phenotype

KW - Prostatic Neoplasms

KW - Receptors, Androgen

KW - Signal Transduction

KW - Transcription, Genetic

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DO - 10.1093/nar/gku281

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JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 10

ER -

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

Abstract

Keywords

UN SDGs

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