UDP glucuronosyltransferase 2B17 is present in the prostate, where it catalyzes 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 affect 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, because
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 Forkhead Box A1 (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 with the -155A allele. Consonant with its capacity to be stimulated by FOXA1, the UGT2B17 -155A allele, compared with 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.