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Prostate. 2006 Jun 15;66(9):911-20.

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

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  • 1Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32816-2364, USA.

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 co-transfected 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-1a, 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 approximately 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.

Copyright 2006 Wiley-Liss, Inc.

PMID:
16541421
[PubMed - indexed for MEDLINE]

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