title: Androgen regulation of 5α-reductase isoenzymes in prostate cancer: implications for prostate cancer prevention.
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.
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ding
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Wang
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Lu
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Jeri
authors.initials: J
authors.lastname: Kim
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D042944:Cholestenone 5 alpha-Reductase / Q000235:genetics / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000728:Androgens; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D003609:Dactinomycin; D042944:Cholestenone 5 alpha-Reductase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548469:SRD5A3 protein, human