Defining splicing factor requirements for androgen receptor variant synthesis in advanced prostate cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE248502 | GEO | 2024/07/25
REPOSITORIES: GEO
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Project description:The androgen receptor splice variant 7 (AR-V7) lacks the ligand-binding domain; is detected with increased frequency in advanced prostate cancer and is postulated to be one crucial mechanism for disease progression and therapeutic resistance to androgen deprivation in castration–resistant prostate cancer (CRPC). Targeting AR-V7 or unique downstream targets could provide novel therapeutic approaches for CRPC. Here, we report that, independent of ligand, AR-V7 binds not only to the androgen-responsive element (ARE) sites inducing canonical AR signaling but also to non-canonical target sites where ligand-stimulated full-length AR (AR-FL) does not bind. These AR-V7 “solo” binding sites are mainly found at gene promoters and are co-occupied by a zinc-finger transcription factor ZFX and the co-activator BRD4, both of which physically interact with AR-V7. Consequently, AR-V7 not only recapitulates AR-FL action without androgen but uniquely regulates transcripts correlating with AR-V7 expression in the TCGA prostate cancer cohort. Mechanistically, ZFX appears to function as a pioneer factor for AR-V7 at solo-binding sites and BRD4 inhibitors but not anti-androgens suppress AR-V7 action at solo-binding sites as well as AR-V7-dependent growth. Additionally, knockdown of ZFX, or two downstream targets uniquely co-activated by AR-V7 (ZNF32 and FZD6), also suppressed growth of AR-V7-dependent CRPC cells. AR-V7 directly activated genes differentiate tumor from normal prostate tissues and predict poor prognosis in patients. Thus AR-V7 has both canonical and non-canonical regulatory functions in CRPC, which may provide new therapeutic avenues.
2018-10-02 | GSE94013 | GEO
Project description:Constitutively active androgen receptor (AR) signaling confers resistance to AR-targeted therapies. Here we show that the ubiquitin-mediated proteolysis pathway plays a critical role in the degradation of AR and its variants, particularly variant 7 (AR-V7). AR/AR-V7 proteinhomeostasis (proteostasis) requires interaction of the E3 ubiquitin ligase STUB1 and HSP70complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 reduces AR/AR-V7 expression which significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason scores prostate tumors. Our results reveal a novel mechanism of AR-V7 modulation via proteostasis which could be targeted to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.
2018-10-05 | GSE120005 | GEO
Project description:Constitutively active androgen receptor (AR) signaling confers resistance to AR-targeted therapies. Here we show that the ubiquitin-mediated proteolysis pathway plays a critical role in the degradation of AR and its variants, particularly variant 7 (AR-V7). AR/AR-V7 proteinhomeostasis (proteostasis) requires interaction of the E3 ubiquitin ligase STUB1 and HSP70complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 reduces AR/AR-V7 expression which significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason scores prostate tumors. Our results reveal a novel mechanism of AR-V7 modulation via proteostasis which could be targeted to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.
2018-10-05 | GSE120004 | GEO
Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone. A total of four metastatic castration-resistant prostate tumor samples from four patients were subjected to RNA-seq. Two samples were positive for androgen receptor splice variant 7 and the other two were negative for this variant.
2014-09-03 | E-GEOD-56701 | biostudies-arrayexpress
Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone.
2014-09-03 | GSE56701 | GEO
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
Project description:Androgen receptor variant 7 (AR-V7) has been proposed to have independent functional roles different from full length AR. Here we study the functional roles of AR-V7 in chemotherapy castration resiatnt prostate cancer models by ChIp-sequencing approaches.
2023-01-12 | GSE214332 | 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 goal of this study was to compare the global transcriptomic effects of knockdown of AR vs inhibition of STAT5 via treatment with IST5-002 in the prostate cancer cell line CWR22Rv1. We knocked down AR with 2 independent shRNAs (or shCtrl). We treated cells for 72 hrs with 0.8 µM IST5-002 (or DMSO control).
2024-03-06 | GSE227612 | GEO