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Effect of p53 knowkdown on genome-wide map of AR-DNA binding

ABSTRACT: We report that p53 knockdown changed AR-DNA binding across the genome. We found fewer AR-binding sites in the absence of p53. Examination of AR-DNA binding after p53 knockdown in LNCaP cells

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas Bair

PROVIDER: E-GEOD-31294 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Inhibition of p53 expression modifies the specificity of chromatin binding by the androgen receptor.

Guseva Natalya V NV Rokhlin Oskar W OW Bair Thomas B TB Glover Rebecca B RB Cohen Michael B MB

Oncotarget 20120201 2

The androgen receptor (AR) is known to play a critical role in prostate cancer (PC). p53 likely also plays a role given that p53 mutations are commonly found in advanced PC, and loss of wild-type protein function contributes to the phenotype of castration-resistant prostate cancer (CRPC). Nevertheless, the extent of the contribution of p53 dysfunction to PC remains unclear. Here we analyze the effects of p53 inhibition in PC cells and show that it has significant consequences for both the intera ...[more]

PMID: 22383394

Similar Datasets

Effect of p53 knowkdown on genome-wide map of AR-DNA binding

Project description:We report that p53 knockdown changed AR-DNA binding across the genome. We found fewer AR-binding sites in the absence of p53.

2012-07-31 | GSE31294 | GEO

Gene Expression in Castration-Resistant C4-2 Cells after AR Knockdown

Project description:Prostate cancer is the most common, lethal malignancy in men. Although androgen withdrawal therapies are used to treat advanced disease, progression to a castration-resistant, end-stage is the usual outcome. In this study, the tested hypothesis was that the androgen receptor remains essential for the growth and viability of castration-resistant disease. Knocking down the androgen receptor in well-established tumors grown in castrated mice caused growth arrest, decreased serum PSA, and frequently regression and total eradication of tumors. Growth control of castration-resistant tumors appeared to be linked to the extent of androgen receptor knockdown, which triggers upregulation of many genes involved in apoptosis, cell cycle arrest, and inhibition of tumorigenesis and protein synthesis. Our findings provide proof of principle that in vivo knockdown of the androgen receptor is a viable therapeutic strategy to control and possibly eradicate prostate cancers that have progressed to the lethal castration-resistant state. C4-2 human prostate cancer cells stably expressing a tetracycline-inducible AR-targeted short hairpin RNA (shRNA) or scrambled shRNA were generated. These two cell lines were incubated in the absence of androgens with or without doxycycline hyclase (DOX). Comparison analysis of the gene expression profiles of C4-2 cells stably expressing AR shRNA + DOX and control cells (AR shRNA - DOX and scrambled shRNA Â± DOX) was conducted to identify differentially regulated genes due to AR knockdown after normalization and data filtering. Genes were considered to be significantly different if the expression in the induced AR shRNA + DOX cells was at least 1.7-fold greater or 1.7-fold less than that seen in the control cells, with P< 0.05.

2010-06-23 | E-GEOD-13332 | biostudies-arrayexpress

TALEN-Engineered AR Gene Rearrangements Reveal Endocrine Uncoupling of Androgen Receptor in Prostate Cancer

Project description:This experiment addressed the question of whether full length Androgen receptor and Androgen Receptor variant ARv567es have similar transciptional activities. The transcriptomes of R1-AD1, a AR full length expressing cell line, are compared in an AR on (1nM DHT) to an AR off (ethanol vehicle) state. R1-D567 was derived from R1-AD1 and modified with TALENs in such a way as to express only AR-V567es. The AR on and off states were induced with a control siRNA (AR on) or a siRNA targeting exon 1 (AR off). R-AD1 was cultured for 24 hours in either base RPMI media with 1nM DHT or ethanol vehichle and RNA extracted. R1-D567 cells were electroporated with control siRNA or siRNA targeting exon 1 of AR and allowed to recover 48 hours and then cultured in base media with 1nM DHT or ethanol for 24 hrs. Each conditon was done in triplicate.

2013-09-01 | E-GEOD-49196 | biostudies-arrayexpress

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

Genome wide analysis of AR binding sites and histone modifications in prostate cancer

Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation.We performed ChIP-seq analysis to investigate the role of AR and histone modifications.In addition, by siRNA mediated knockdown of AR-associated factors, changes of AR-binding sites in prostate cancer cells were analyzed.. ChIP-sequence analysis of AR and its associated factors in prostate cancer cells

2015-02-08 | E-GEOD-62492 | biostudies-arrayexpress

Next Generation Sequencing Facilitates Quantitative Analysis of effect of knockdown of GATA2 on AR binding sites

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare AR binding activity in LNCaP cells with and without knockdown of GATA2. Methods: LNCaP cells between passage number 32-34 were used for assay. Cells are transfected with GATA2 specific or nonspecific siRNA and ChIP was performed, the ChIP producted was further used to generate library with illumina ChIP-seq kit. Hi-seq 2500 was used for sequencing and the data was analyzed by MACs for peaks. Results: GATA2 knockdown lead to changes of AR binding activity , in most AR binding sites, AR shows decreased bindig activity. Only small percent sites show increased binding. Conclusions: Our study represents the first detailed analysis of the relationship between GATA2 and AR binding in whole genomic DNA.These results demostrate GATA2 play a critical role in AR activity in prostate cancer. LNCaP cells was used as cell model were treated with specific GATA2 siRNA.Library was sequenced using Illumina HI-seq 2500.

2014-01-21 | E-GEOD-52725 | biostudies-arrayexpress

Activation of P-TEFb by androgen receptor-regulated enhancer RNAs in androgen deprivation conditions [ChIP-Seq]

Project description:Androgen receptor (AR) is required for castration resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain poorly understood. Here, we identify a group of AR-regulated enhancer RNAs (e.g. PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDX) and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb and promotes in cis and trans gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). To avoid the total Pol II changing by PSA eRNA. We measured the total Pol II using N20 and 8WG16 antibodies with or without PSA eRNA knocking down. To avoid the AR binding changes by PSA eRNA, we also measured the AR binding using AR N20 antibodies with or without PSA eRNA knocking down. Androgen receptor (AR) binding sites in human prostate cancer cell lines, C4-2, were studied using ChIP-seq. Total Pol II Ser-2p and AR binding sites in human prostate cancer cell lines C4-2 with or without PSA eRNA knockdown, were studied using ChIP-seq. ChIP enriched DNA were sequenced using Illumina HiSeq 2500and input DNA were sequenced using Illumina HiSeq 2000.

2016-02-12 | E-GEOD-71704 | biostudies-arrayexpress

Genome wide mapping of AR and its associated factors in prostate cancer

Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation.We performed ChIP-seq analysis to investigate the role of AR and its associated factors such as coregulators or collaborating factors.In addition, by siRNA mediated knockdown of such factors, changes of AR-binding sites in prostate cancer cells were analyzed. ChIP-sequence analysis of AR and its associated factors in prostate cancer cells

2014-11-14 | E-GEOD-58428 | biostudies-arrayexpress

Activation of P-TEFb by enhancer RNAs associated with lethal prostate cancer [ChIP-seq]

Project description:Castration resistant prostate cancer (CRPC) is a lethal disease. Sustained aberrant activation of androgen receptor (AR) becomes a central mechanism that contributes to endocrine therapy resistance. Here, we demonstrate that AR-bound enhancer RNAs (AR-eRNAs), including eRNA of the KLK3 (or PSA) gene, are upregulated in human CRPC cells and patient tissues. By enhancing C-termine domain (CTD) serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p), PSA eRNA acts in cis to promote PSA mRNA transcription and in trans to induce mRNA expression of a large set of genes involved in androgen action, cell cycle progression and tumorgenesis. Accordingly, we demonstrate that PSA eRNA binds in vitro and in vivo to CYCLIN T1, a regulatory subunit of the positive transcription elongation factor b (P-TEFb) complex that mediates Pol II-Ser2p. To identify the PSA eRNAâ??s functions on the Pol II-Ser2p and CYCLINT1 in the CRPC C4-2 cells, we detected the Pol II-Ser2p and CYCLINT1 ChIP-seq with or without PSA eRNA knockdown in the C4-2 cells. Moreover, to rule out the AR binding changes and identify the AR binding sites around the new genes, we detected the AR ChIP-seq in LNCaP and C4-2 cells with or without the androgen. Androgen receptor (AR) binding sites in human prostate cancer cell lines, LNCaP and C4-2, were studied using ChIP-seq. Pol II Ser-2p and CYCLINT1 binding sites in human prostate cancer cell lines C4-2 with or without PSA eRNA knockdown, were studied using ChIP-seq. ChIP enriched and input DNA were sequenced using Illumina HiSeq 2000.

2016-02-12 | E-GEOD-65066 | biostudies-arrayexpress

The cistrome and transcriptome landscape of androgen receptor splice variants in castration-resistant prostate cancer cells

Project description:The spliced variant forms of androgen receptor (AR-Vs) have been identified recently in castration-resistant prostate cancer (CRPC) cell lines and clinical samples. Here we identified the cistrome and transcriptome landscape of AR-Vs in CRPC cell lines and determine the clinical significance of AR variants regulated gene.The AR variants binding sites can be identified in 22Rv1 cell line in the absence of androgen. Knocking down full-length AR (AR-FL) doesn't affect AR-Vs binding sites in genome-wide. A set of genes were identified to be regulated uniquely by AR-Vs, but not by AR-FL in androgen-depleted condition. Integrated analysis showed that some genes may be modulated by AR-Vs directly. Unsupervised clustering analysis demonstrated that AR variants gene signature can separate not only the benign and malignant prostate tissue, but also the localized prostate cancer and metastatic CRPC specimens. Some genes modulated uniquely by AR variants were also identified to correlate with the Gleason Pattern of prostate cancer and PSA failure. We conclude that AR spliced variants bind to DNA independent of full-length AR, and can modulate a unique set of genes which is not regulated by full-length AR in the absence of androgen. AR variants gene signature correlate with CRPC and prostate cnacer disease progress. Androgen receptor (AR) binding sites in human prostate cancer 22Rv1 cell lines were studied using ChIP-seq. ChIP enriched and input DNA were sequenced using Illumina HiSeq 2000.

2014-09-10 | E-GEOD-58478 | biostudies-arrayexpress

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