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

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

32 Scopus citations

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)	6256-6269
Number of pages	14
Journal	Nucleic Acids Research
Volume	42
Issue number	10
DOIs	https://doi.org/10.1093/nar/gku281
State	Published - Jun 2 2014
Externally published	Yes

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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), 6256-6269. 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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AU - Sharma, Naomi L.

AU - Massie, Charlie E.

AU - Butter, Falk

AU - Mann, Matthias

AU - Bon, Helene

AU - Ramos-Montoya, Antonio

AU - Menon, Suraj

AU - Stark, Rory

AU - Lamb, Alastair D.

AU - Scott, Helen E.

AU - Warren, Anne Y.

AU - Neal, David E.

AU - Mills, Ian G.

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N2 - 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.

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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SN - 0305-1048

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EP - 6269

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 10

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

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