Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17 genes.
BACKGROUND
Enhanced androgen receptor (AR) activity by increased testosterone availability may play important roles in prostate cancer progressing to castration resistant state. Comparison of expression profiles in androgen dependent and independent prostate tumors demonstrated a marked increase of the expression of UDP-glucuronosyltransferase 2B15 (UGT2B15), an androgen catabolic enzyme. We investigated mechanisms controlling the differential expression of UGT2B15 and B17 in response to androgen treatments.


METHODS
Gene expression was determined by RT-PCR. The association of AR with UGT2B15/B17 genes was determined by Chromatin immuno-precipitation (CHIP). RNA interference was used to knock-down gene expression.


RESULTS
UGT2B15 and B17 genes were not expressed in AR negative prostate cancer cell lines, PC3 and DU145, while they were expressed in AR positive cell lines, LNCaP, LNCaP-abl (an androgen independent LNCaP sub-line), and VCaP. The expression levels of UGT2B15/B17 were up-regulated in LNCaP-abl comparing to those in LNCaP. These results suggest the requirement of AR for the expression of UGT2B15/B17. Treatment with DHT down-regulated the expression of UGT2B15/B17 in LNCaP in a time and dose dependent manner and this down-regulation was competitively antagonized by flutamide and bicalutimide, suggesting a pathway mediated by AR. Further CHIP experiments demonstrated the direct interaction of AR with the promoter regions of UGT2B15/B17 genes. Knocking down AR expression in LNCaP significantly reduced the expression of UGT2B15/B17 and completely inhibited the DHT-induced down-regulation of UGT2B15/B17 genes.


CONCLUSIONS
We demonstrated that UGT2B15 and B17 are primary androgen-regulated genes and AR is required for both their basal expression and their androgen-regulated expression.
Bao
Bo-Ying
BY
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Chuang
Bin-Fay
BF
Wang
Qianben
Q
Sartor
Oliver
O
Balk
Steven P
SP
Brown
Myles
M
Kantoff
Philip W
PW
Lee
Gwo-Shu Mary
GS
D059002:Androgen Receptor Antagonists; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
D059002:Androgen Receptor Antagonists; D015778:Minor Histocompatibility Antigens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human