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J. Biol. Chem., Vol. 283, Issue 8, 4834-4840, February 22, 2008

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Ubiquitination by TOPORS Regulates the Prostate Tumor Suppressor NKX3.1^*

Bin Guan, Pooja Pungaliya, Xiang Li, Carlos Uquillas, Laura N. Mutton, Eric H. Rubin, and Charles J. Bieberich^¶1

From the Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland 21250, the Departments of Medicine and Pharmacology, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, and the ^¶Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

The NKX3.1 gene located at 8p21.2 encodes a homeodomain-containing transcription factor that acts as a haploinsufficient tumor suppressor in prostate cancer. Diminished protein expression of NKX3.1 has been observed in prostate cancer precursors and carcinomas. TOPORS is a ubiquitously expressed E3 ubiquitin ligase that can ubiquitinate tumor suppressor p53. Here we report interaction between NKX3.1 and TOPORS. NKX3.1 can be ubiquitinated by TOPORS in vitro and in vivo, and overexpression of TOPORS leads to NKX3.1 proteasomal degradation in prostate cancer cells. Conversely, small interfering RNA-mediated knockdown of TOPORS leads to an increased steady-state level and prolonged half-life of NKX3.1. These data establish TOPORS as a negative regulator of NKX3.1 and implicate TOPORS in prostate cancer progression.

Received for publication, October 17, 2007 , and in revised form, December 11, 2007.

^* This work was supported by Congressionally Directed Medical Research Program Grants DAMD-03-1-0091 and W81XWH-07-1-0232 (to C. J. B.) and NCI National Institutes of Health Grant CA99951 (to E. H. 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 To whom correspondence should be addressed: Dept. of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250. Tel.: 410-455-3125; Fax: 410-455-3875; E-mail: bieberic{at}umbc.edu.

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