Abstract
The enzyme 5α-reductase, which converts testosterone to dihydrotestosterone (DHT), performs key functions in the androgen receptor (AR) signaling pathway. The three isoenzymes of 5α-reductase identified to date are encoded by different genes: SRD5A1, SRD5A2, and SRD5A3. In this study, we investigated mechanisms underlying androgen regulation of 5α-reductase isoenzyme expression in human prostate cells. We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type-specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation. In addition, our results suggest that AR is recruited to a negative androgen response element (nARE) on the promoter of SRD5A3 in vivo and directly binds to the nARE in vitro. The different expression levels of 5α-reductase isoenzymes may confer response or resistance to 5α-reductase inhibitors and thus may have importance in prostate cancer prevention.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
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3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
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Androgens / pharmacology*
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Animals
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Cell Line, Tumor
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Cholestenone 5 alpha-Reductase / genetics
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Cholestenone 5 alpha-Reductase / metabolism*
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Dactinomycin / pharmacology
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Dihydrotestosterone / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Organ Specificity / drug effects
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Promoter Regions, Genetic / genetics
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Prostatic Neoplasms / enzymology*
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / prevention & control*
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Protein Binding / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Androgen / metabolism
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Response Elements / genetics
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Transcription, Genetic / drug effects
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Xenograft Model Antitumor Assays
Substances
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AR protein, human
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Androgens
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Isoenzymes
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Membrane Proteins
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RNA, Messenger
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Receptors, Androgen
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Dihydrotestosterone
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Dactinomycin
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Cholestenone 5 alpha-Reductase
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3-Oxo-5-alpha-Steroid 4-Dehydrogenase
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SRD5A3 protein, human