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Androgen regulation of prostasin gene expression is mediated by sterol‐regulatory element‐binding proteins and SLUG
Author(s) -
Chen Mengqian,
Chen LiMei,
Chai Karl X.
Publication year - 2006
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20325
Subject(s) - lncap , slug , transfection , biology , sterol regulatory element binding protein , gene expression , transcription factor , hek 293 cells , microbiology and biotechnology , downregulation and upregulation , complementary dna , messenger rna , endocrinology , medicine , cell culture , cancer research , gene , cancer cell , genetics , cancer
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 ∼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. Prostate 66: 911–920, 2006. © 2006 Wiley‐Liss, Inc.