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J. Biol. Chem., Vol. 282, Issue 44, 31954-31963, November 2, 2007

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Androgen Receptor Regulation of the Versican Gene through an Androgen Response Element in the Proximal Promoter^*

Jason T. Read¹, Maziar Rahmani¹, Seti Boroomand, Sima Allahverdian, Bruce M. McManus, and Paul S. Rennie²

From the Prostate Center, Vancouver General Hospital, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V6T 2B5 and The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Research Institute, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6Z 1Y6, Canada

Versican, one of the key components of prostatic stroma, plays a central role in tumor initiation and progression. Here, we investigated promoter elements and mechanisms of androgen receptor (AR)-mediated regulation of the versican gene in prostate cancer cells. Using transient transfection assays in prostate cancer LNCaP and cervical cancer HeLa cells engineered to express the AR, we demonstrate that the synthetic androgen R1881 and dihydrotestosterone stimulate expression of a versican promoter-driven luciferase reporter vector (versican-Luc). Further, both basal and androgen-stimulated versican-Luc activities were significantly diminished in LNCaP cells, when AR gene expression was knocked down using a short hairpin RNA. Methylation-protection footprinting analysis revealed an AR-protected element between positions +75 and +102 of the proximal versican promoter, which strongly resembled a consensus steroid receptor element. Electrophoretic mobility shift and supershift assays revealed strong and specific binding of the recombinant AR DNA binding domain to oligonucleotides corresponding to this protected DNA sequence. Site-directed mutagenesis of the steroid receptor element site markedly diminished R1881-stimulated versican-Luc activity. In contrast to the response seen using LNCaP cells, R1881 did not significantly induce versican promoter activity and mRNA levels in AR-positive prostate stromal fibroblasts. Interestingly, overexpression of -catenin in the presence of androgen augmented versican promoter activity 10- and 30-fold and enhanced versican mRNA levels 2.8-fold in fibroblasts. In conclusion, we demonstrate that AR transactivates versican expression, which may augment tumor-stromal interactions and may contribute to prostate cancer progression.

Received for publication, March 12, 2007 , and in revised form, August 10, 2007.

^* This work was supported by grants from the Terry Fox Foundation (to P. S. R.), The Prostate Cancer Research Foundation of Canada (to P. S. R. and J. T. R.), and the Heart and Stroke Foundation of British Columbia and Yukon (to M. R. and B. M. M.), by Doctoral Research Awards from the Heart and Stroke Foundation of Canada (to M. R.), by a Graduate Fellowship of the University of British Columbia (to M. R.), and by a Doctoral Award from the Ministry of Health and Medical Education of Iran (to M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia V6T 2B5, Canada. Tel.: 604-875-4818; Fax: 604-875-5654; E-mail: prennie{at}interchange.ubc.ca.

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