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Selective Targeting of PARP2 Inhibits Androgen Receptor Signaling and Prostate Cancer Growth Through Disruption of FOXA1 Function

ABSTRACT: Selective Targeting of PARP2 Inhibits Androgen Receptor Signaling and Prostate Cancer Growth Through Disruption of FOXA1 Function

PROVIDER: PRJNA470767 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7142050.fastq.gz	Fastqsanger.gz
	SRR7142060.fastq.gz	Fastqsanger.gz
	SRR7142070.fastq.gz	Fastqsanger.gz
	SRR7142041.fastq.gz	Fastqsanger.gz
	SRR7142051.fastq.gz	Fastqsanger.gz

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Genome-wide occupation of AR, FOXA1, and H3K27AC in LNCaP cells treated with selective PARP2 inhibitor UPF-1069

Project description:Androgen receptor (AR) signaling is a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated transcription provides new opportunities for therapeutic intervention. We have previously discovered that a genetic variant in one of the DNA repair genes, PARP2, is associated with aggressive PCa. Here, we show that a high expression level of PARP2 in PCa tumors is associated with high Gleason scores and biochemical recurrence using The Cancer Genome Atlas (TCGA) dataset. Functional studies reveal that PARP2 enhances AR-mediated gene expression through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to the enhancer regions genome-wide in PCa cells. Selective targeting of PARP2, but not PARP1, by genetic or pharmacological means blocks interaction between PARP2 and FOXA1, which in turn attenuates AR-mediated transcription and inhibits AR-positive PCa growth. SIGNIFICANCE: Current anti-androgens act through blocking ligand binding or inhibiting androgen synthesis. Selective targeting of PARP2 may provide a novel therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA repair defect status and, more importantly, when direct AR-targeted therapies fail.

2019-06-24 | GSE114274 | GEO

Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer

Project description:This SuperSeries is composed of the following subset Series: GSE30622: Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [Expression Array] GSE30623: Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [ChIP_seq, DHS_seq] Refer to individual Series

2011-09-13 | E-GEOD-30624 | biostudies-arrayexpress

Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [ChIP_seq, DHS_seq]

2011-09-14 | E-GEOD-30623 | biostudies-arrayexpress

Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [Expression Array]

Project description:We report the dual role of FoxA1 in androgen receptor recruitment to the chromatin of androgen responsive prostate cancer cell line LNCaP-1F5 using ChIP-sequencing. Depletion of FoxA1 reprograms both androgen and glucocorticoid receptor recruitment and subsequent gene expression. The ChIP-seq has been performed using AR, FoxA1, GR, H3K4me2 antibodies. We have also mapped the DNaseI-hypersensitive sites (DHS) using deep sequencing. LNCaP-1F5 cells were depleted of FoxA1 using siRNAs. Parental cells and FoxA1 depleted cells (siFoxA1) were treated with vehicle or 100 nM DHT or (100 nM DEX) for 24 hours followed by RNA isolation and hybridization to Illumina arrays. All the experiments have been performed in biological duplicates. Parental cells treated with DHT (or DEX) were analyzed for differentially expressed genes compared to vehicle treated parental cells. Similarly siFoxA1 cells treated with DHT (or DEX) were analyzed for differentially expressed genes compared to vehicle treated siFoxA1 cells.

2011-09-13 | E-GEOD-30622 | biostudies-arrayexpress

Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [ChIP_seq, DHS_seq]

2011-09-14 | GSE30623 | GEO

Dual Role of FoxA1 in Androgen Receptor Binding to Chromatin, Androgen Signaling and Prostate Cancer [Expression Array]

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FoxA1 inhibits androgen receptor expression and suppresses prostate cancer metastasis [LNCaP, ChIP-seq]

Project description:FoxA1 has been shown critical for prostate development and prostate-specific gene expression regulation. In addition to its well-established role as an AR pioneering factor,several studies have recently revealed significant AR binding events in prostate cancer cells with FoxA1 knockdown. Furthermore, the role of FoxA1 itself in prostate cancer has not been carefully examined. Thus, it is important to understand the role of FoxA1 in prostate cancer and how it interacts with AR signaling. To address these questions, we generated LNCaP cells with stable FoxA1 knockdown. We performed AR/FoxA1 ChIP-seq and microarray analysis of these cells. ChIP_Seq examination of AR and FoxA1 binding sites in LNCaP shCtrl and shFoxA1 cells

2014-06-02 | E-GEOD-37345 | biostudies-arrayexpress

FoxA1 inhibits androgen receptor expression and suppresses prostate cancer metastasis [DU145, ChIP-seq]

Project description:FoxA1 has been shown critical for prostate development and prostate-specific gene expression regulation. In addition to its well-established role as an AR pioneering factor,several studies have recently revealed significant AR binding events in prostate cancer cells with FoxA1 knockdown. Furthermore, the role of FoxA1 itself in prostate cancer has not been carefully examined. Thus, it is important to understand the role of FoxA1 in prostate cancer and how it interacts with AR signaling. ChIP-Seq examination of AR and FoxA1 binding sites, FAIRE-seq detection of open chromatin genomic regions in DU145 AR +/- FOXA1 cells

2014-06-02 | E-GEOD-47987 | biostudies-arrayexpress

Selective targeting of PARP-2 inhibits androgen receptor signaling and prostate cancer growth through disruption of FOXA1 function.

Project description:Androgen receptor (AR) is a ligand-activated transcription factor and a key driver of prostate cancer (PCa) growth and progression. Understanding the factors influencing AR-mediated gene expression provides new opportunities for therapeutic intervention. Poly(ADP-ribose) Polymerase (PARP) is a family of enzymes, which posttranslationally modify a range of proteins and regulate many different cellular processes. PARP-1 and PARP-2 are two well-characterized PARP members, whose catalytic activity is induced by DNA-strand breaks and responsible for multiple DNA damage repair pathways. PARP inhibitors are promising therapeutic agents that show synthetic lethality against many types of cancer (including PCa) with homologous recombination (HR) DNA-repair deficiency. Here, we show that, beyond DNA damage repair function, PARP-2, but not PARP-1, is a critical component in AR transcriptional machinery through interacting with the pioneer factor FOXA1 and facilitating AR recruitment to genome-wide prostate-specific enhancer regions. Analyses of PARP-2 expression at both mRNA and protein levels show significantly higher expression of PARP-2 in primary PCa tumors than in benign prostate tissues, and even more so in castration-resistant prostate cancer (CRPC) tumors. Selective targeting of PARP-2 by genetic or pharmacological means blocks interaction between PARP-2 and FOXA1, which in turn attenuates AR-mediated gene expression and inhibits AR-positive PCa growth. Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.

| S-EPMC6642419 | biostudies-literature

Selective Disruption of Core Regulatory Transcription

Project description:Selective Disruption of Core Regulatory Transcription

| PRJNA494422 | ENA