Androgen regulation of prostasin gene expression is mediated by sterol-regulatory element-binding proteins and SLUG

    Authors

    M. Q. Chen; L. M. Chen;K. X. Chai

    Comments

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    Abbreviated Journal Title

    Prostate

    Keywords

    prostate cancer; dihydrotestosterone; transcription repressors; SREBP; SNAIL; growth factor; ACID SYNTHASE EXPRESSION; REPRESSES E-CADHERIN; SERINE-PROTEASE; BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; SNAIL; CELLS; RECEPTOR; LOCALIZATION; ACTIVATION; Endocrinology & Metabolism; Urology & Nephrology

    Abstract

    BACKGROUND. Prostasin is downregulated in hormone-refractory prostate cancers (HRPC). The mechanisms by which androgens regulate prostasin expression are unclear. METHODS. LNCaP cells were treated with dihydrotestosterone (DHT), and mRNA expression of prostasin, SREBPs, SNAIL, and SLUG was examined by real-time PCR following reverse transcription. A human prostasin promoter was evaluated in HEK-293 cells cotransfected with transcription factor cDNAs. Regulation of endogenous prostasin expression by transfected SREBP-2 or SLUG was evaluated. Expression of SNAIL and SLUG mRNA in DU-145 cells treated with epidermal growth factor (EGF) was examined. RESULTS. Prostasin mRNA expression in LNCaP cells was not responsive to DHT treatment. DHT marginally upregulated mRNA expression of SREBP-1c, SREBP-2, and SNAIL, but not SREBP-la, while dramatically increased SLUG mRNA expression, in a dose-dependent manner. Co-transfection of prostasin promoter and SREBP cDNA in HEK-293 cells resulted in stimulation of promoter activity at similar to twofold by SREBP-1c, and up to sixfold by SREBP-2; while co-transfection with SNAIL or SLUG cDNA resulted in repression of promoter activity to 43% or 59%, respectively. Co-transfection of the SLUG cDNA negated SREBP-2's stimulation of prostasin promoter in a dose-dependent manner. Transfection of an SREBP-2 cDNA in HEK-293 and DU-145 resulted in upregulation of prostasin while transfection of a SLUG cDNA in LNCaP repressed prostasin expression. EGF upregulated SNAIL and SLUG mRNA in DU-145. CONCLUSIONS. DHT regulates prostasin expression in prostate cells via SREBP stimulation and SLUG repression of prostasin promoter. SLUG is upregulated by DHT and EGF, providing a molecular mechanism by which epithelial cell-specific genes are silenced during prostate cancer development and progression.

    Journal Title

    Prostate

    Volume

    66

    Issue/Number

    9

    Publication Date

    1-1-2006

    Document Type

    Article

    Language

    English

    First Page

    911

    Last Page

    920

    WOS Identifier

    WOS:000237839700003

    ISSN

    0270-4137

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