title: SUMOylation modulates the transcriptional activity of androgen receptor in a target gene and pathway selective manner.
abstract: 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 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. Fittingly, SUMOylation mutant AR cells proliferate faster and are more sensitive to apoptosis. Moreover, ChIP-seq analyses show that the SUMOylation can modulate the chromatin occupancy of AR on many loci in a fashion that parallels their differential androgen-regulated expression. De novo motif analyses reveal that FOXA1, C/EBP and AP-1 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 AR's interaction with the chromatin and the receptor's target gene selection.
authors: Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
authors: Päivi
authors: P
authors: Sutinen
authors: Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
authors: Marjo
authors: M
authors: Malinen
authors: Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
authors: Sami
authors: http://orcid.org/0000-0002-6083-2402
authors: S
authors: Heikkinen
authors: Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland Department of Pathology, Kuopio University Hospital, Kuopio, Finland jorma.palvimo@uef.fi.
authors: Jorma J
authors: JJ
authors: Palvimo
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: D011944:Receptors, Androgen