RT Journal Article
SR Electronic
T1 A novel polymorphism in a FOXA1 binding site of the human UDP glucuronosyltransferase 2B17 gene modulates promoter activity and is associated with altered levels of circulating androstane-3α, 17β-diol glucuronide.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.065953
DO 10.1124/mol.110.065953
A1 Dong Gui Hu
A1 Dione A Gardner-Stephen
A1 Gianluca Severi
A1 Philip A Gregory
A1 Joanna Treloar
A1 Graham G Giles
A1 Dallas English
A1 John Hopper
A1 Wayne D Tilley
A1 Peter I MacKenzie
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/07/13/mol.110.065953.abstract
AB UDP glucuronosyltransferase 2B17 is present in the prostate, where it catalyses the addition of glucuronic acid to testosterone and dihydrotestosterone and their metabolites androsterone and androstane-3α, 17β-diol. Hence, changes in UGT2B17 gene expression may impact on the capacity of the prostate to inactivate and eliminate male sex hormones. In this work, we identify a prevalent polymorphism, -155G/A, in the proximal promoter of the UGT2B17 gene. This polymorphism modulates UGT2B17 promoter activity, as luciferase-gene reporter constructs containing the -155A allele were 13-fold more active than those containing the -155G allele in prostate cancer LNCaP cells. The -155G/A polymorphism is contained within a putative binding site for the transcription factor FOXA1. Using gene reporter, electromobility shift and chromatin immunoprecipitation analyses, we show that FOXA1 binds to this site and stimulates the UGT2B17 promoter. Furthermore, down-regulation of FOXA1 in LNCaP cells substantially reduces UGT2B17 mRNA levels. The binding of FOXA1 and subsequent stimulation of the UGT2B17 promoter is greatly reduced in the presence of the -155G allele compared to the -155A allele. Consonant with its capacity to be stimulated by FOXA1, the UGT2B17 -155A allele, in comparison to the -155G allele, is associated with higher levels of circulating androstane-3α, 17β-diol glucuronide. Although the initial phases of prostate cancer are androgen-dependent and UGT2B17 inactivates androgens, there was no association of the UGT2B17 -155G/A polymorphism with prostate cancer risk. In summary, this work identifies FOXA1 as an important regulator of UGT2B17 expression in prostate cancer LNCaP cells and identifies a polymorphism that alters this regulation.