Androgen receptor splicing variant 7 (ARv7) promotes DNA damage response in prostate cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1161179 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30669050_1.fastq.gz | Fastqsanger.gz | |||
| SRR30669050_2.fastq.gz | Fastqsanger.gz | |||
| SRR30669051_1.fastq.gz | Fastqsanger.gz | |||
| SRR30669051_2.fastq.gz | Fastqsanger.gz | |||
| SRR30669052_1.fastq.gz | Fastqsanger.gz |
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Project description:In the treatment of patients with locally advanced prostate cancer (PCa), androgen deprivation therapy (ADT) significantly enhances the efficacy of radiotherapy by weakening the DNA damage response (DDR) pathway. Recently, several studies have suggested that androgen receptor splicing variants (ARvs) may mediate a compensatory DDR pathway when canonical androgen receptor (AR) signaling is inhibited, thus contributing to the resistance of some patients to this combinational treatment. However, the specific roles of certain ARvs as well as the detailed mechanism of how ARvs regulate the DDR are not well understood. Here, we demonstrated that AR splicing variant 7 (ARv7), which is the most abundant form of ARvs, significantly promotes the DDR of PCa cells under severe DNA damage independent of its parental AR by using the ionizing radiation (IR) and doxorubicin (Dox)-treated cell models. Mechanistically, ARv7 is sufficient to upregulate both the homologous recombination (HR) and the nonhomologous end joining (NHEJ) pathways by forming a positive regulatory loop with poly ADP-ribose polymerase 1 (PARP1). Moreover, the presence of ARv7 impairs the synergistic effect between AR antagonists and poly ADP-ribose polymerase (PARP) inhibitor, which has been recently shown to be a promising future treatment strategy for metastatic castration resistant prostate cancer (mCRPC). Combined, our data indicate that constitutively active ARv7 not only contributes to radioresistance after ADT, but may also serve as a potential predictive biomarker for assessing the efficacy of novel PARP inhibitor-based therapy in PCa.
2024-09-14 | GSE277204 | GEO
Project description:Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
2025-01-01 | GSE277606 | GEO
Project description:Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
2025-01-01 | GSE252842 | GEO
Project description:Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
2025-01-01 | GSE252897 | GEO
Project description:Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
2025-01-01 | GSE252843 | GEO
Project description:Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
2025-01-01 | GSE252840 | GEO
Project description:Androgen receptor (AR) splice variants, of which ARv7 is most common, are increased in prostate cancer (PC) that develops resistance to androgen signaling inhibitor drugs, but the extent to which they drive AR activity, and whether they have novel functions or dependencies, remain to be determined. We generated a subline of VCaP PC cells (VCaP16) that was resistant to the AR inhibitor enzalutamide (ENZ) and found that AR activity was independent of the full length AR (ARfl), despite its continued high level expression, and was instead driven by ARv7. The ARv7 cistrome and transcriptome in these cells mirrored that of the ARfl in VCaP cells, although ARv7 chromatin binding was weaker, and strong ARv7 binding sites correlated with higher affinity ARfl binding sites across multiple models and clinical samples. Notably, although ARv7 expression increased rapidly in response to ENZ, there was a long lag before it gained chromatin binding and transcriptional activity. This lag was associated with an increase in chromatin accessibility, with the AR and nuclear factor I (NFI) motifs being most enriched at these more accessible sites. Moreover, the transcriptional effects of combined NFIB and X knockdown versus ARv7 knockdown were highly correlated. These findings indicate that ARv7 can drive the AR program, but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
2025-01-01 | GSE252841 | GEO
Project description:Endocrine therapies in prostate cancer (PCa) treatment block androgen receptor (AR) function, but are palliative as tumors progress to a lethal, castration-resistant state (CRPC). CRPC remains dependent on AR signaling, which can act through the full-length AR (ARfl) or constitutively active splice variants, e.g. ARv7. We show here that both ARfl and ARv7 bind to the same genomic region and heterodimerize in a CRPC cell line model, but regulate distinct transcriptomes. ARv7, unlike ARfl, preferentially represses transcription and demonstrates an increased affinity for co-repressors, decreased chromatin residence time and lower dependence on FOXA1 binding. We identified a group of ARv7-repressed genes, including the UDP-galactosyltransferase B4GALT1 that are down-regulated during PCa progression and important for CRPC growth. In conclusion, we propose that ARv7 acts as a transcriptional repressor of genes that limit proliferation, a function that should be targeted in CRPC patients.
2018-11-02 | GSE106559 | GEO
Project description:Endocrine therapies in prostate cancer (PCa) treatment block androgen receptor (AR) function, but are palliative as tumors progress to a lethal, castration-resistant state (CRPC). CRPC remains dependent on AR signaling, which can act through the full-length AR (ARfl) or constitutively active splice variants, e.g. ARv7. We show here that both ARfl and ARv7 bind to the same genomic region and heterodimerize in a CRPC cell line model, but regulate distinct transcriptomes. ARv7, unlike ARfl, preferentially represses transcription and demonstrates an increased affinity for co-repressors, decreased chromatin residence time and lower dependence on FOXA1 binding. We identified a group of ARv7-repressed genes, including the UDP-galactosyltransferase B4GALT1 that are down-regulated during PCa progression and important for CRPC growth. In conclusion, we propose that ARv7 acts as a transcriptional repressor of genes that limit proliferation, a function that should be targeted in CRPC patients.
2018-11-02 | GSE106560 | GEO
Project description:Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance occurs when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or when constitutively active splice variants lacking the androgen binding domain entirely (e.g. ARV7) is expressed. In this study, we are reporting the discovery of novel AR-NTD covalent inhibitor 1‐chloro‐3‐[(5‐([(2S)‐3‐chloro‐2‐hydroxypropyl]amino)naphthalen‐1‐yl)amino]propan‐2‐ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and its known coactivators and interactors, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule AR-NTD inhibitor for the treatment of CRPC.
2021-07-28 | GSE173331 | GEO