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Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [ChIP-exo]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143906 | GEO | 2021/07/07

REPOSITORIES: GEO

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Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC) [RNA-seq]

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

AR signalling in castration resistant prostate cancer (CRPC)

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

AR-V7 Targets in Castration-Resistant Prostate Cancer (CRPC) Cell Line

Project description:In order to define the genes responsible for the growth and survival of a human castration-resistant prostate cancer cell line, a short term (doxycycline inducible) knockdown system was developed and utilized. Three independent 22Rv1 cell isolates were derived for each of the following doxycycline-inducible shRNAs (shGFP, shAR3, and shVav3) (AR3 = AR-V7). The cells were grown in androgen depleted conditions, plus or minus doxycycline, for three days. RNA from the 18 samples was then sent to the University of Miami Genetics Core for RNA Integrity Number (RIN) evaluation and microarray analysis. Genes differentially regulated by AR-V7 knock-down or VAV3 knock-down were explored as downstream targets of AR-V7 or VAV3, respectively.

2018-08-16 | GSE104572 | GEO

AR-V7 targets the oncogenic genes in castration resistant prostate cancer. [ChIP]

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

Heterogeneity of Androgen Receptor Splice Variant-7 (AR-V7) Protein Expression and Response to Therapy in Castration Resistant Prostate Cancer (CRPC)

Project description:Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival (OS) from endocrine therapies in castration resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 biology and expression in prostate cancer (PC) tissue. Following generation and validation of a novel AR-V7 antibody for immunohistochemistry (IHC); nuclear AR-V7 protein expression was determined for 358 primary prostate samples (358 patients) and 293 metastatic biopsies (194 patients). Associations with disease progression, nuclear AR full length (AR-FL) expression, response to abiraterone and/or enzalutamide, and gene signatures (from three independent cohorts) was determined.

2018-10-19 | GSE118435 | GEO

Effect of over-expression of AR-V7 in MDA-MB-453 breast cancer cells

Project description:The effect of transient transfection of a construct designed to over-express the androgen receptor (AR) variant AR-V7 on gene expression in MDA-MB-453 cells was assessed using Affymetrix Gene 2.0 ST arrays. Transfection of an AR-expressing construct or an empty construct served as controls. AR-V7, AR or empty vector was transfected into MDA-MB-453 cells. Cells were treated with vehicle control or DHT.

2015-02-10 | E-GEOD-65738 | biostudies-arrayexpress

Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC)

Project description:Androgen Receptor splice variant V7 (AR-V7) mediates AR signalling in castration resistant prostate cancer (CRPC)

| PRJNA602078 | ENA

AR-V7 targets the oncogenic genes in castration resistant prostate cancer. [RNA]

Project description:To identify the AR-V7 target genes in human prostate cancer, two cell lines (LNCaP, LNCaP95) were subjected to RNA-seq analysis.

2020-11-02 | GSE122923 | GEO

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

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

Role of androgen receptor splice variant 7 (AR-v7) in prostate cancer resistance to 2nd generation androgen receptor signaling inhibitors

Project description:Since its discovery, there has been one central issue of significant clinical relevance related to expression of the truncated androgen receptor splice variant-7 (AR-v7), which lacks the C-terminal ligand binding domain and thus acquires ligand-independent transcriptional activity in castration-resistant prostate cancer (CRPC). That question is whether AR-v7 is simply a marker of enhanced AR transcriptional activity characteristic of resistance to 2nd generation androgen receptor signaling inhibitors (ARSi) like Abiraterone and Enzalutamide, or whether it drives lethal resistance to ARSi. To address this question, the present study utilized 4 independently derived CRPC patient-derived xenografts in which the genetic and phenotypic changes could be followed before and after the development of ARSi resistance. This allowed evaluation of the correlation between acquired resistance to ARSi and changes in the expression levels of full length AR (AR-FL) vs. AR-v7 during this process. The combined results document that elevated expression of AR-FL alone is sufficient for Abiraterone- but not Enzalutamide-resistance. This is true even if AR-FL has a gain-of-function mutation. Furthermore, Enzalutamide-resistance is consistently correlated with the acquisition of AR-v7 expression. To directly test the requirement for AR-v7 expression in ARSi-refractory CRPC, CRISPR-Cas9 knockout of AR-FL and/or AR-v7 in LNCaP-95 cells was performed to evaluate in vitro and in vivo growth responses. These results document that AR-v7 drives Enzalutamide-resistance and focuses the critical need to develop therapeutic options to prevent and/or inhibit AR-v7 driven lethal progression of CRPC.

2020-10-11 | GSE149433 | GEO

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