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Chromatin relaxation is a feature of advanced prostate cancer [FAIRE-Seq]

ABSTRACT: Altered patterns of transcription factor (TF) binding are now accepted as a hallmark of many aggressive cancers including prostate and breast cancers1,2. This implies that underlying global changes in chromatin accessibility may drive cancer progression, as previously hypothesized3-5. In addition there are epigenetic readers such as bromodomain containing protein 4 (BRD4), which have been shown to associate with these TFs6-8 and also to contribute to aggressive cancers of many types8,9 including prostate cancer (PC)6,10. Here we show for the first time that formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq) applied to human prostate tumors tissue can define castrate-resistant prostate cancer (CRPC) and can be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor (AR) overexpression alone is a primary driver for chromatin relaxation and that this effect can be reversed using bromodomain inhibitors. We also report that bromodomain-containing proteins (BRDs) are overexpressed in advanced CRPCs and that ATAD2 and BRD2 have prognostic value. In conclusion, this is the first study demonstrating a major impact of BRDs on chromatin accessibility in CRPC in patient samples. Consequently, targeting bromodomains provides a compelling rational for combination therapy in which BRD-mediated TF binding is enhanced or modified as cancer progresses. FAIRE-seq study for LNCaP and VCaP prostate cancer cell lines hormone starved or treated with R1881, and human prostate tissue samples from benign prostate hyperplasia (BPH), primary prostate cancer (PC), and castrate resistant prostate cancer (CRPC) patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73988 | GEO | 2017/06/06

SECONDARY ACCESSION(S): PRJNA298679

REPOSITORIES: GEO

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Chromatin relaxation is a feature of advanced prostate cancer [expression]

Project description:Altered patterns of transcription factor (TF) binding are now accepted as a hallmark of many aggressive cancers including prostate and breast cancers1,2. This implies that underlying global changes in chromatin accessibility may drive cancer progression, as previously hypothesized3-5. In addition there are epigenetic readers such as bromodomain containing protein 4 (BRD4), which have been shown to associate with these TFs6-8 and also to contribute to aggressive cancers of many types8,9 including prostate cancer (PC)6,10. Here we show for the first time that formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq) applied to human prostate tumors tissue can define castrate-resistant prostate cancer (CRPC) and can be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor (AR) overexpression alone is a primary driver for chromatin relaxation and that this effect can be reversed using bromodomain inhibitors. We also report that bromodomain-containing proteins (BRDs) are overexpressed in advanced CRPCs and that ATAD2 and BRD2 have prognostic value. In conclusion, this is the first study demonstrating a major impact of BRDs on chromatin accessibility in CRPC in patient samples. Consequently, targeting bromodomains provides a compelling rational for combination therapy in which BRD-mediated TF binding is enhanced or modified as cancer progresses. Expression profile of LNCaP and VCaP prostate cancer cell lines treated with synthetic androgen R1881 with or without concomitant treatment with the pan-BET bromodomain inhibitor JQ1.

2017-06-06 | GSE73930 | GEO

The androgen receptor induces a distinct transcriptional program in castration resistant prostate cancer in man

Project description:The androgen receptor (AR) is the major transcriptional driver of prostate cell growth in man. For the first time, we define AR targets in prostate cancer (PC) tissue representing progression from treatment-naive to castrate-resistant disease (CRPC). We employed chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies. We uncovered an AR transcriptional network not observed in cultured cells, with significant over-representation of MYC, E2F and STAT binding sites, progenitor cell gene signatures and targets which regulate metabolism, cell cycle and steroid biosynthesis. We identified AR targets unique to CRPC tissue, with a subset over-expressed in CRPC and predictive of clinical outcome, highlighting persistence of AR signalling. Our data support a model whereby endocrine and paracrine signals converge on the AR in PC tissue to drive oncogenic transcriptional programs, highlighting the critical role of cellular context in the regulation of target selection and gene expression. chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies

2013-01-04 | E-GEOD-28219 | biostudies-arrayexpress

The ETS family member GABPa mediates the development of castrate-resistant prostate cancer (ChIP-Seq)

Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPÃ¡, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. VCaP prostate cancer cells and Jurkat lymphoma cells were studied for the ETS factors ERG and GABPa binding sites. Each sample was compared to its input.

2014-05-21 | E-GEOD-49091 | biostudies-arrayexpress

The androgen receptor induces a distinct transcriptional program in castration resistant prostate cancer in man

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Identification of the RB loss-induced transcriptome in prostate cancer [RNA]

Project description:The retinoblastoma protein (RB) is preferentially lost in the progression to castrate resistant prostate cancer (CRPC). However, the alterations associated with such loss have been scantly described. The current study aims to provide molecular mechanisms underlying Rb loss-driven CRPC phenotypes

2018-02-19 | GSE94863 | GEO

Identification of the RB loss-induced E2F1 cistrome in prostate cancer [ChIP-seq]

2018-02-22 | GSE94958 | GEO

BET Bromodomain Inhibition Blocks the Function of a Critical AR-Independent Master Regulator Network in Lethal Prostate Cancer

Project description:BET bromodomain inhibitors are known to block prostate cancer cell survival through suppression of c-Myc and androgen receptor (AR) function. However, little is known about other transcriptional modulators whose function is blocked by these drugs and the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency may be increasing. In this study we determined that BET bromodomain inhibition suppresses survival of a diverse set of CRPC cell models, including those that do not express the AR or in which c-Myc is not suppressed. To identify additional transcriptional regulators whose suppression contributes to the anti-tumor effects of BET bromodomain inhibition, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1, measured genome-wide gene expression changes, and then used the Master Regulator Inference Algorithm (MARINa). This approach identified transcriptional regulators whose function is blocked by JQ1 and whose suppression recapitulates the effects of BET bromodomain inhibition. High Expression of these Master Regulators in aggressive human CRPC demonstrates their clinical relevance.

2019-03-20 | GSE98069 | GEO

Hes6 drives a critical AR transcriptional program to induce castration resistant prostate cancer through activation of an E2F1-mediated cell cycle network

Project description:Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. Here we show that Hes6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for other transcription factors including E2F1. In the clinical setting, we have uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted with restoration of sensitivity to castration. AR and E2F1 ChIPseq from multiple simultaneous LNCaP cell replicates with and without bicalutamide

2014-04-17 | E-GEOD-49832 | biostudies-arrayexpress

The ETS family member GABPa mediates the development of castrate-resistant prostate cancer (BeadChip)

Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPá, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. Cells were made to either overexpress GABPa or have it knocked down; these conditions also had empty vector and non-targetting controls respectively. All four treatments were carried out with and without androgen for the LNCaP and c42b cell lines. Biological and technical replicates were used.

2014-05-21 | E-GEOD-49083 | biostudies-arrayexpress

The ETS family member GABPa mediates the development of castrate-resistant prostate cancer (ChIP-Seq)

Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPá, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes.

2014-05-21 | GSE49091 | GEO

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