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Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer

ABSTRACT: Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer

PROVIDER: PRJNA298680 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2646270.fastq.gz	Fastqsanger.gz
	SRR2646280.fastq.gz	Fastqsanger.gz
	SRR2646261.fastq.gz	Fastqsanger.gz
	SRR2646271.fastq.gz	Fastqsanger.gz
	SRR2646262.fastq.gz	Fastqsanger.gz

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Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer [expression]

Project description:Prostate cancer is the most common non-cutaneous cancer in men. The androgen receptor (AR) a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signalling networks have been shown to be altered in patients and to influence AR activity. The oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies, but its impact on AR activity in prostate cancer remains elusive. In this study we assessed the impact of clinically relevant levels of c-Myc overexpression on AR activity and transcriptional output. We found that c-Myc and the AR share a substantial amount of binding sites, which exhibit enhancer-like characteristics. Interestingly, c-Myc overexpression altered global AR chromatin occupancy and antagonised a subset of androgen-induced genes. Furthermore, c-Myc overexpression modified histone marks, most notably H3K4me1 and H3K27me3. Lastly, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 and GNMT, in patient samples.

2017-04-14 | GSE73917 | GEO

Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer [ChIP-Seq]

Project description:c-Myc overexpression LNCaP cells were treated with R1881 or R1881+Doxycycline (to induce c-Myc overexpression) and ChIP-seq studies were performed using antibodies against c-Myc, AR, H3K4me1, H3K4me3, H3K27ac and H3K27m3 Prostate cancer is the most common non-cutaneous cancer in men. The androgen receptor (AR) a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signalling networks have been shown to be altered in patients and to influence AR activity. The oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies, but its impact on AR activity in prostate cancer remains elusive. In this study we assessed the impact of clinically relevant levels of c-Myc overexpression on AR activity and transcriptional output. We found that c-Myc and the AR share a substantial amount of binding sites, which exhibit enhancer-like characteristics. Interestingly, c-Myc overexpression altered global AR chromatin occupancy and antagonised a subset of androgen-induced genes. Furthermore, c-Myc overexpression modified histone marks, most notably H3K4me1 and H3K27me3. Lastly, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 and GNMT, in patient samples.

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Overexpression of c-Myc antagonises transcriptional output of the androgen receptor in prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-04-14 | GSE73995 | GEO

GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

Project description:Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting p300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.

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GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

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GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

Project description:GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

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GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

Project description:GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistance

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c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks.

Project description:Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

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Effect of castration, bicalutamide, and enzalutamide on androgen receptor binding in Hi-Myc mouse prostate tumors

Project description:Effect of castration, bicalutamide, and enzalutamide on androgen receptor binding in Hi-Myc mouse prostate tumors

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