An unorthodox AR addiction drives enzalutamide resistance in prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA561348 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10010001_1.fastq.gz | Fastqsanger.gz | |||
| SRR10010001_2.fastq.gz | Fastqsanger.gz | |||
| SRR10010002_1.fastq.gz | Fastqsanger.gz | |||
| SRR10010002_2.fastq.gz | Fastqsanger.gz | |||
| SRR10010003_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:An unorthodox AR addiction drives enzalutamide resistance in prostate cancer (ChIP-Seq)
| PRJNA561351 | ENA
Project description:An unorthodox AR addiction drives enzalutamide resistance in prostate cancer (RNA-Seq)
| PRJNA561352 | ENA
Project description:Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.
2020-08-20 | GSE136129 | GEO
Project description:Acquisition of resistance to the next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castrate-resistant prostate cancer (CRPC). Most ENZ-resistant (ENZ-R) CRPCs are androgen receptor (AR)-positive (CRPCAR+), but often negative for prostate-specific antigen (PSA), a well-established surrogate of AR activity, implying the emergence of AR-indifferent disease. Through genome-wide ChIP-seq and RNA-seq profiling in disease-relevant ENZ-R CRPCAR+ cells, we identified a unique set of gained AR binding sites (ARBS-G) lacking the canonical DNA binding elements of AR and the pioneer factor FOXA1. ARBS-G loci are highly enriched with CpG islands and significantly overlapped with the binding sites of the unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. Expression of CXXC5 and its downstream targets including inhibitor of differentiation-1 (ID1) was upregulated in ENZ-R CRPCAR+ cell lines, patient-derived xenografts (PDXs) and patient specimens. Genetic depletion of AR, CXXC5 or ID1 restored ENZ sensitivity in human ENZ-R CRPCAR+ cells. Most importantly, ENZ-R CRPCAR+ cells, organoids, xenografts and PDXs were invariably hypersensitive to the novel BET-CBP/p300 dual inhibitor NEO2734. These results reveal that ENZ-R CRPCAR+ cancers are only indifferent to the canonical AR (cAR) activity, but remain addictive to the noncanonical AR (ncAR) function which is selectively vulnerable upon dual inhibition of CBP/p300 and BET family proteins.
2020-08-20 | GSE136128 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-08-20 | GSE136130 | GEO
Project description:Molecular mechanisms underlying resistance to androgen deprivation therapy (ADT) and, in particular, to antiandrogen Enzalutamide, in treating castration-resistant prostate cancer (CRPC), remain incompletely understood. Through screening >120 CRPC patient samples, we observed 3 expression patterns of androgen receptor (AR) protein: primarily nuclear (nuc-AR), mixed nuclear/cytoplasmic expression (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling in 4 models (i.e., LNCaP, VCaP, LAPC4, and LAPC9) recapitulated the 3 AR expression patterns in castration-resistant tumors developed from parental androgen-dependent tumors. Strikingly, although the 3 CRPC models that retained AR expression (LNCaP, VCaP, and LAPC4) responded, to different levels and in different kinetics, to Enzalutamide, the AR-/lo LAPC9 CRPC was completely refractory to Enzalutamide. By combining whole-genome RNA-Seq and biochemical analyses together with experimental combinatorial therapy in the LNCaP and LAPC9 models, we identified BCL-2 as a critical therapeutic target in both AR+/hi and AR-/lo, Enzalutamide-resistant CRPC models.
2018-08-01 | GSE88752 | GEO
Project description:Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
| S-EPMC7943793 | biostudies-literature
Project description:In order to identify AR-repressed genes that are activated by enzalutamide in t-NEPC cell lines, we cultured enza-resistant MR42D cells in the absence of enzalutamide for 72 hours, then added back either enzalutamide or vehicle and cultured for an additional 24 hours. Then we performed chromatin immunoprecipitation sequencing (ChIP-seq) pulling down AR, BRD4, and H3K27Ac. To identify potential NEPC genes suppressed by the AR, we compared AR DNA occupancy from the vehicle and enzalutamide treatments to identify regions where AR was evicted in response to enzalutamide. Similarly to determine the role of histone acetylation on NEPC gene activation in t-NEPC lines, we examined differential DNA-binding of the BRD4 acetylated lysine reader, and differential acetylation of the active enhancer mark H3K27Ac in response to enzalutamide treatment.
2021-06-22 | GSE147875 | GEO
Project description:Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) â?? the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. RNA-seq profiles of prostate cancer cell lines to understand gene expression associated with enzalutamide treatment
2016-06-10 | E-GEOD-69896 | biostudies-arrayexpress
Project description:Enzalutamide (formerly MDV3100 and available commercially as Xtandi), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: (1) binding of androgens to AR, (2) AR nuclear translocation, and (3) association of AR with DNA. Here we used Affymetrix human genome microarray technology to investigate the global programme of gene expression of LNCaP cells in response to enzalutamide alone and in the context of DHT-stimulated androgen receptor gene expression. LNCaP cells were grown in RPMI 1640 supplemented with 5% hormone depleted FBS and treated with vehicle (control sample) , DHT (100 nM), enzalutamide (1 or 10 M-BM-5M) or DHT (100 nM) plus enzalutamide (1 or 10 M-BM-5M)for 16 hours for RNA extraction and hybridization. Each condition was done in triplicate.
2013-04-01 | E-GEOD-44905 | biostudies-arrayexpress