Similar Datasets
Project description:Investigation of the AR cistrome in response to RB depletion in castration-resistant prostate cancer
| PRJNA719828 | ENA
Project description:These studies examine the consequence of RB loss on E2F1 function across prostate cancer progression.
2021-04-26 | GSE154191 | GEO
Project description:Castration-resistant PCa (CRPC) remains androgen receptor (AR) dependent. There are multiple mechanisms for reactivation of AR including expression of the constitutively active AR splice variant, AR-V7 (AR3). Earlier studies suggest that though the variants regulate many of the same genes as AR, they also have unique targets. Another argument is that the variant is a “weak” AR without unique targets. We have used an LN95 cell line that endogenously expresses AR and a low level of AR-V7 to compare the activities of the isoforms and to determine whether there is differential regulation of target genes. The transcriptomes for AR and AR-V7 were identified using RNA-Seq.
2021-12-31 | GSE184676 | GEO
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
Project description:To elucidate the AR-V7 role, we performed ChIP-seq on H3K4me1, H3K4me3, H3K27ac, and AR antibody recognizing the N-terminus of AR and AR splice variants (AR-Vs) using LNCaP and LNCaP95 cells. We showed 399 AR-V7 targeted regions in LNCaP95, most of the AR-V7 target regions could be commonly activated by hormone stimulated AR. However, 22 regions were identified as AR-V7 specific regions. In addition, we show here that AR-V7 can transcript in the ligand independent manner in LNCaP95, unlike LNCaP. We identified the AR-V7 target gene contributing to the CRPC progression.
2020-11-02 | GSE122922 | GEO
Project description:CRPC remains AR dependent. There are multiple mechanisms for reactivation of AR including expression of constitutively active AR splices variant AR-V7 (AR3). Earlier studies suggest that though the variants regulate many of the same genes as AR, they also have unique targets. Another argument is that the variant is a “weak” AR. We have used an LNCaP cell line that expresses AR-V7 in response to doxycycline (LNCaP AR-V7) to compare the activities of the two isoforms and to identify differential regulation of target genes. We also used VCaP cell line that expresses AR-V7 in response to doxycycline (VCaP AR-V7) to validate the activities of the two isoforms in an alternative prostate cancer cell line. The transcriptomes for AR and AR-V7 in these cell lines were identified using RNA-Seq.
2021-01-21 | GSE143905 | GEO
Project description:CRPC remains AR dependent. There are multiple mechanisms for reactivation of AR including expression of constitutively active AR splices variant AR-V7 (AR3). Earlier studies suggest that though the variants regulate many of the same genes as AR, they also have unique targets. Another argument is that the variant is a “weak” AR. We have used an LNCaP cell line that expresses AR-V7 in response to doxycycline to compare DNA interactions of the two isoforms and to identify differential regulation of target genes. ChIP-exo method was used to map AR and AR-V7 interaction with DNA in LNCaP engineered cell line (LNCaP AR-V7) at single base resolution.
2021-07-07 | GSE143906 | GEO
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
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 ± 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
Project description:The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7-driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7-driven prostate tumors.
2018-05-31 | GSE99378 | GEO