Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: PM-CM-$ivi Sutinen

PROVIDER: E-GEOD-54104 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner.

Sutinen Päivi P Malinen Marjo M Heikkinen Sami S Palvimo Jorma J JJ

Nucleic acids research 20140630 13

Androgen receptor (AR) plays an important regulatory role in prostate cancer. AR's transcriptional activity is regulated by androgenic ligands, but also by post-translational modifications, such as SUMOylation. To study the role of AR SUMOylation in genuine chromatin environment, we compared androgen-regulated gene expression and AR chromatin occupancy in PC-3 prostate cancer cell lines stably expressing wild-type (wt) or doubly SUMOylation site-mutated AR (AR-K386R,K520R). Our genome-wide gene ...[more]

PMID: 24981513

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Project description:Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LNCaP prostate cancer (PC) cell line, one overexpressing AR 2M-bM-^@M-^S3-fold and the other 4M-bM-^@M-^S5-fold compared with the control cells. We used chromatin immunoprecipitation (ChIP) and deep-sequencing (seq) to identify AR-binding sites (ARBSs). We found that the number of ARBSs and the AR-binding strength were positively associated with the level of AR when cells were stimulated with low concentrations of androgens. In cells overexpressing AR, the chromatin binding of the receptor took place in 100-fold lower concentration of the ligand than in control cells. We conM-oM-,M-^Armed the association of AR level and chromatin binding in two PC xenografts, one containing AR gene ampliM-oM-,M-^Acation with high AR expression, and the other with low expression. By combining the ChIP-seq and expression proM-oM-,M-^Aling, we identiM-oM-,M-^Aed AR target genes that are upregulated in PC. Of them, the expression of ZWINT, SKP2 (S-phase kinase-associated protein 2 (p45)) and FEN1 (M-oM-,M-^Bap structure-speciM-oM-,M-^Ac endonuclease 1) was demonstrated to be increased in CRPC, while the expression of SNAI2 was decreased in both PC and CRPC. FEN1 protein expression was also associated with poor prognosis in prostatectomy-treated patients. Finally, the knock-down of FEN1 with small interfering RNA inhibited the growth of LNCaP cells. Our data demonstrate that the overexpression of AR sensitizes the receptor binding to chromatin, thus, explaining how AR signaling pathway is reactivated in CRPC cells. Examination of AR binding with 9 cell line samples + control and 2 xenograft samples + control. ChIPseq with AR antibody in 3 different LNCaP derivative cell lines overexpressing AR upon treatment with different androgen concentrations and 2 different tumor xenografts expressing different AR levels.

Dataset Information

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

Publications

SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner.

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