Androgen receptor amplification is reflected in the transcriptional responses of Vertebral-Cancer of the Prostate cells.
Androgen receptor (AR) is overexpressed in a majority of castration-resistant prostate cancers, but most of the cell model studies addressing AR function have been conducted in LNCaP prostate cancer cells expressing unamplified AR levels. Here, we have compared the responses of various types of AR ligands towards a pattern of AR target genes and chromatin binding sites in Vertebral-Cancer of the Prostate (VCaP) cells and LNCaP cells. In keeping with the AR gene amplification in VCaP cells, our analyses show that these cells contain ≥10-fold receptor mRNA and protein than LNCaP cells. Loading of the agonist-occupied AR onto chromatin regulatory sites and expression of several AR target genes, including their basal expression, were stronger in VCaP cells than LNCaP cells. Bicalutamide displayed a trend towards agonism in VCaP cells. Bicalutamide also evoked AR-chromatin interaction, whereas diarylthiohydantoin antiandrogen RD162 was inert with this respect both in VCaP and LNCaP cells. These results support the notion that the AR protein level translates into augmented occupancy of AR-regulated enhancers and target gene activity in prostate cancer cells.
Makkonen
Harri
H
Institute of Biomedicine, University of Eastern Finland, Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
Kauhanen
Miia
M
Jääskeläinen
Tiina
T
Palvimo
Jorma J
JJ
D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D017373:Cyproterone Acetate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D000728:Androgens; D000813:Anilides; D002843:Chromatin; D009570:Nitriles; C540715:RD162 compound; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; D015741:Metribolone; D017373:Cyproterone Acetate; C053541:bicalutamide