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J. Biol. Chem., Vol. 281, Issue 7, 4002-4012, February 17, 2006

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SUMO-3 Enhances Androgen Receptor Transcriptional Activity through a Sumoylation-independent Mechanism in Prostate Cancer Cells^*

From the University of Toledo, Department of Biological Sciences, Toledo, Ohio 43606

Androgens are important for male sexual development, which depend on the cognate receptor, the androgen receptor. The transcriptional activity of the androgen receptor, like other nuclear receptors, is regulated by accessory proteins that can have either positive or negative effects. Through a yeast functional screen, we have identified SUMO-3 as a regulator of androgen receptor activity in prostate cancer cells. SUMO-3 is one of three eukaryotic proteins that become post-translationally conjugated to their target proteins in a manner analogous to the attachment of ubiquitin. In primary prostate epithelial cells, PrEC, and the prostate cancer cells, PC-3, SUMO-3 has a weak negative effect on androgen receptor transcriptional activity. In contrast, SUMO-3 and it close relative SUMO-2 strongly enhance transactivation by endogenous androgen receptor in LNCaP cells. This positive effect is observed in both androgen-dependent and androgen-independent LNCaP cells. Interestingly, SUMO-1, unlike SUMO-3 and SUMO-2, can inhibit, but not stimulate, androgen receptor activity. Mutational analysis of the androgen receptor and SUMO-3 demonstrates that the SUMO-3-positive activity does not depend on either the sumoylation sites of the androgen receptor or the sumoylation function of SUMO-3. Stable overexpression of SUMO-3 in LNCaP cells significantly enhances the androgen-dependent proliferation of these cells. Additionally, siRNA-mediated repression of SUMO-2 significantly inhibits the growth of both androgen-dependent and -independent LNCaP cells. Collectively, these results suggest (i) a novel mechanism for elevating AR activity through the switch of SUMO-3 from a weak negative regulator in normal prostate cells to a strong positive regulator in prostate cancer cells and (ii) a proliferative role for SUMO-3 and SUMO-2 in the growth of prostate cancer cells that is independent of sumoylation of the androgen receptor.

Received for publication, August 22, 2005 , and in revised form, November 21, 2005.

^* This work was supported by grants from the National Institutes of Health (DK51274) and Ohio Cancer Research Associates. 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 Present address: Medical University of Ohio, 3000 Arlington Ave., Toledo, OH 43614.

² Present address: Harvard Medical School, 330 Brookline Ave., Boston, MA 02215.

³ To whom correspondence should be addressed: Dept. of Biological Sciences, University of Toledo, Toledo, OH 43606. Tel.: 419-530-1553; Fax: 419-530-7737; E-mail: lshemsh{at}uoft02.utoledo.edu.

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