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Effect of MPC309 (AR-targeting Multivalent Peptoid Conjugate) treatment on gene expression in LNCaP-ABL cells (castration-resistant prostate cancer cell line) in comparison to Vehicle control and another AR ligand, Ethisterone (partial agonist): ATAC-Seq

ABSTRACT: We conducted ATAC-seq on LNCaP-abl cells treated overnight with either vehicle (DMSO), MPC309, Backbone, DHT or Enzalutamide to reveal areas of accessible chromatin. Our results indicated that the vast majority of peaks (>46,000) were shared among all groups. Notwithstanding, MPC309 incited some chromatin restructuring, as evidenced by the unique 8,750 open chromatin sites seen in cells treated with MPC309 as opposed to those treated with the vehicle. Analysis of transcription factor (TF) binding-motifs around regions of chromatin exclusively open in MPC309-treated cells exposed NR-binding motifs (GRE, PRE, ARE, AR-half sites). This indicates the potential for MPC309-bound AR to interact with chromatin at AR-specific locations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236288 | GEO | 2023/07/11

REPOSITORIES: GEO

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Effect of MPC309 (AR-targeting Multivalent Peptoid Conjugate) treatment on gene expression in LNCaP-ABL cells (castration-resistant prostate cancer cell line) in comparison to Vehicle control and another AR ligand, Ethisterone (partial agonist): ChIP-Seq

Project description:To establish wehther the genes stimulated or inhibited by MPC309 are directly influenced by the AR, we conducted ChIP-seq of AR from LNCaP-abl cells that had been treated with vehicle (DMSO), MPC309, Backbone, DHT, or Enzalutamide overnight. Our results revealed a more pronounced AR presence in cells exposed to MPC309 and DHT as compared to control groups and those treated with enzalutamide, reinforcing the idea that MPC309 facilitates distinct AR interactions with chromatin. Genes linked with AR occupancy mirrored similar GO terms as those seen in RNA-seq experiments. Out of the 251 genes repressed by MPC309 compared to controls (vehicle and backbone), 246 (98%) had an AR binding site within 15 kb upstream or downstream of the gene promoter. Similarly, of the 405 genes stimulated by MPC309, 387 (96%) had an AR binding site within 15 kb of the gene promoter. These observations suggest that the gene regulation driven by MPC309 stems from AR interactions with chromatin, resulting in varying impacts on gene expression compared to DHT or enzalutamide, consequently inhibiting the growth of prostate cancer cells.

2023-07-11 | GSE236287 | GEO

Project description:Effect of MPC309 (an AR-targeting Multivalent Peptoid Conjugate) treatment on gene expression in LNCaP-ABL cells (a castration-resistant prostate cancer cell line) in comparison to Vehicle control and another well-known AR ligand, Ethisterone (partial agonist). Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPCs) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. To determine if the effects of MPC309 differ from those of ethisterone alone, we conducted RNA-seq analysis on LNCaP-abl cells. These cells were treated overnight with either a control vehicle (DMSO), MPC309, or ethisterone. Our analysis revealed that there was minimal overlap in the genes regulated by MPC309 and ethisterone alone.

2023-07-11 | GSE236088 | GEO

Project description:Prostate cancers evolve to resist androgen receptor (AR) pathway inhibitors, such as enzalutamide, leading to castration resistance due to sustained AR expression and function. In response, we have designed a novel strategy to regulate the AR and suppress castration-resistant prostate cancer (CRPC) by employing multivalent peptoid conjugates (MPCs). These conjugates comprise multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic framework. To pinpoint the genes and pathways impacted by MPC309, we performed RNA-sequencing on LNCaP-abl cells, which were treated overnight with various agents: vehicle (DMSO), peptoid backbone, MPC309, dihydrotestosterone (an AR activator), or enzalutamide (an AR inhibitor commonly used clinically). Our findings revealed unique gene expression patterns (transcriptomes) in cells exposed to each compound, indicating that MPC309 may be a new AR ligand influencing the AR transcriptional response.

2023-07-11 | GSE236286 | GEO

Genome-wide analysis of androgen receptor (AR) SUMOylation effects on gene expression (HEK293).

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Isogenic HEK293 cells stably expressing wild-type AR (wtAR) or SUMOylation-defective AR (AR-K2R) were treated 24 h with 10 nM R1881 or vehicle (EtOH). All conditions were performed in triplicate. The effect on gene expression was assessed by microarray.

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Genome-wide analysis of androgen receptor (AR) SUMOylation effects on gene expression (PC-3).

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. PC-3 cells stably expressing wild-type AR (wtAR) or SUMOylation-defective AR (AR-K2R) were treated 16 h with 10 nM R1881 or vehicle (EtOH). All conditions were performed in triplicate. The effect on gene expression was assessed by microarray.

2014-07-03 | E-GEOD-54104 | biostudies-arrayexpress

Genome-wide analysis of SUMOylation effects on androgen receptor (AR) binding in HEK293 cells (ChIP-seq)

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Androgen receptor (AR) genomic binding was studied in wild-type AR (wtAR) or SUMOylation-deficient AR (AR-K2R) stably expressing cells HEK293 cells, in biological dublicates. Cells were treated 40 min either with 10 nM R1881 or EtOH (vehicle) and input was used as control (FRT_input GSM1176703).

2014-07-03 | E-GEOD-54109 | biostudies-arrayexpress

Genome-wide analysis of SUMOylation effects on androgen receptor (AR) binding in PC-3 cells (ChIP-seq)

Project description:Androgen receptor (AR) plays an important regulatory role during prostate cancer development. ARM-bM-^@M-^Ys transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications. To study the role of the AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer and HEK293 cell lines stably expressing wild-type (wt) or SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene expression analyses reveal that the SUMOylation modulates the AR function in a target gene and pathway selective manner. The transcripts that are differentially regulated by androgen and SUMOylation are linked to cellular movement, cell death, cellular proliferation, cellular development and cell cycle. In line with these data, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation modulates the chromatin occupancy of AR on many loci in a fashion that parallels with their differential androgen-regulated expression. De novo motif analyses show that other transcription factor-binding motifs are differentially enriched at the wtAR- and the AR-K386R,K520R-preferred genomic binding positions. Taken together, our data indicate that SUMOylation does not simply repress the AR activity, but it regulates ARM-bM-^@M-^Ys interaction with the chromatin and the receptorM-bM-^@M-^Ys target gene selection. Androgen receptor (AR) genomic binding was studied in wild-type AR (wtAR) or SUMOylation-deficient AR (AR-K2R) stably expressing cells PC-3 cells, in biological dublicates. Cells were treated 1h either with 10 nM R1881 or vehicle and inputs were used as controls.

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Effects of RUNX1 knockdown in AR signaling

Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. We identified RUNX1 is an androgen-regulated gene. In order to investigate the RUNX1 function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siRUNX1 treatment. We also treated cells with vehicle or androgen to analyzed the effects of RUNX1 on AR function.

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