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Research ArticleArticle

A Novel Polymorphism in a Forkhead Box A1 (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

Dong Gui Hu, Dione Gardner-Stephen, Gianluca Severi, Philip A. Gregory, Joanna Treloar, Graham G. Giles, Dallas R. English, John L. Hopper, Wayne D. Tilley and Peter I. Mackenzie
Molecular Pharmacology October 2010, 78 (4) 714-722; DOI: https://doi.org/10.1124/mol.110.065953
Dong Gui Hu
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Dione Gardner-Stephen
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Gianluca Severi
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Philip A. Gregory
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Joanna Treloar
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Graham G. Giles
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Dallas R. English
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John L. Hopper
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Wayne D. Tilley
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Peter I. Mackenzie
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Abstract

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.

Footnotes

  • The work was supported by funding from the National Health and Medical Research Council of Australia [Grant 426705].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065953.

  • ABBREVIATIONS:

    AR
    androgen receptor
    UGT
    UDP-glucuronosyltransferase
    LNCaP
    lymph node carcinoma of the prostate
    DHT
    dihydrotestosterone
    R1881
    methyltrienolone
    FOXA1
    Forkhead Box A1
    SNP
    single-nucleotide polymorphisms
    PCR
    polymerase chain reaction
    VCaP
    vertebral cancer of the prostate
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    bp
    base pair(s)
    EMSA
    electrophoretic mobility shift assay
    PSA
    prostate-specific antigen
    ChIP
    chromatin immunoprecipitation
    qPCR
    quantitative real-time PCR
    siRNA
    small interfering RNA
    RT
    reverse transcription
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    T/E
    testosterone glucuronide/epitestosterone glucuronide
    HNF
    hepatocyte nuclear factor
    Pbx
    pre-B-cell homeobox
    FXR
    farnesoid X receptor.

  • Received April 28, 2010.
  • Accepted July 13, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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A Novel Polymorphism in a Forkhead Box A1 (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
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Research ArticleArticle

A Novel Polymorphism in a Forkhead Box A1 (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

Dong Gui Hu, Dione Gardner-Stephen, Gianluca Severi, Philip A. Gregory, Joanna Treloar, Graham G. Giles, Dallas R. English, John L. Hopper, Wayne D. Tilley and Peter I. Mackenzie
Molecular Pharmacology October 1, 2010, 78 (4) 714-722; DOI: https://doi.org/10.1124/mol.110.065953

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Research ArticleArticle

A Novel Polymorphism in a Forkhead Box A1 (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

Dong Gui Hu, Dione Gardner-Stephen, Gianluca Severi, Philip A. Gregory, Joanna Treloar, Graham G. Giles, Dallas R. English, John L. Hopper, Wayne D. Tilley and Peter I. Mackenzie
Molecular Pharmacology October 1, 2010, 78 (4) 714-722; DOI: https://doi.org/10.1124/mol.110.065953
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