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Rapid CommunicationShort Communication

Forkhead Box Protein A1 Regulates UDP-Glucuronosyltransferase 2B15 Gene Transcription in LNCaP Prostate Cancer Cells

Dong Gui Hu and Peter I. Mackenzie
Drug Metabolism and Disposition December 2010, 38 (12) 2105-2109; DOI: https://doi.org/10.1124/dmd.110.035436
Dong Gui Hu
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Peter I. Mackenzie
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Abstract

The UDP-glucuronosyltransferases (UGTs) 2B15 and 2B17 are the major UGTs involved in the inactivation and elimination of the active androgens, dihydrotestosterone and testosterone. Although regulation of these UGT genes by various endogenous and exogenous ligands, including steroid hormones and bile acids, is well documented, the mechanisms controlling their basal gene expression are poorly understood. We recently reported that Forkhead box protein A1 (FOXA1) regulates the basal expression of the UGT2B17 gene in prostate cancer cells. In this study, we show that FOXA1 also regulates basal expression of the UGT2B15 gene in the prostate cell line LNCaP (lymph node carcinoma of the prostate). FOXA1 binds to a site −208 to −217 base pairs relative to the UGT2B15 translation start site, as shown by electromobility shift and chromatin immunoprecipitation assays. Mutation of this site prevents binding and substantially decreases basal UGT2B15 promoter activity. Silencing of FOXA1 expression by small interfering RNA significantly reduced UGT2B15 transcript levels, further confirming a crucial role of FOXA1 in controlling UGT2B15 gene expression. Because local inactivation of active androgens by UGT2B15 and UGT2B17 has been shown to be a major determinant of androgen response and signaling activity, regulation of the UGT2B15 and UGT2B17 genes by FOXA1 may have an important role in the maintenance of androgen homeostasis within prostate cancer cells.

Footnotes

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

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

    doi:10.1124/dmd.110.035436.

  • ABBREVIATIONS:

    HSD
    hydroxysteroid dehydrogenase
    DHT
    dihydrotestosterone
    ADT
    androsterone
    3α-diol
    5α-androstane-3α,17β-diol
    UGT
    UDP-glucuronosyltransferase
    R1881
    17β-hydroxy-17α-methyl-19-norandrost-4,9,11-trien-3-one
    FOX
    Forkhead box
    PCR
    polymerase chain reaction
    FBS
    fetal bovine serum
    EMSA
    electrophoretic mobility shift assay
    ChIP
    chromatin immunoprecipitation
    RT-qPCR
    reverse transcription-quantitative real-time PCR
    HNF
    hepatocyte nuclear factor
    siRNA
    small interfering RNA
    bp
    base pair
    SNP
    single nucleotide polymorphism
    ERα
    estrogen receptor α
    rRNA
    ribosomal RNA
    LNCaP
    lymph node carcinoma of the prostate
    GW4064
    3-(2,6-dichlorophenol)-4-(3′-carboxy-2-chlorostilben-4-yl-)oxymethyl-5-isopropyl-isoxazole.

  • Received July 13, 2010.
  • Accepted August 23, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Rapid CommunicationShort Communication

Forkhead Box Protein A1 Regulates UDP-Glucuronosyltransferase 2B15 Gene Transcription in LNCaP Prostate Cancer Cells

Dong Gui Hu and Peter I. Mackenzie
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2105-2109; DOI: https://doi.org/10.1124/dmd.110.035436

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Rapid CommunicationShort Communication

Forkhead Box Protein A1 Regulates UDP-Glucuronosyltransferase 2B15 Gene Transcription in LNCaP Prostate Cancer Cells

Dong Gui Hu and Peter I. Mackenzie
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2105-2109; DOI: https://doi.org/10.1124/dmd.110.035436
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