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Research Articles: Therapeutics, Targets, and Development

SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

¹ Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California; Departments of ² Molecular and Clinical Pharmacology, and ³ Immunology, City of Hope, Duarte National Medical Center, Duarte, California; and ⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China

Requests for reprints: David K. Ann, Department of Clinical and Molecular Pharmacology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-359-8111, ext. 64967; Fax: 626-471-7204. E-mail: dann{at}coh.org

Abstract

The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasome–dependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation. Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2. [Mol Cancer Ther 2008;7(4):923–34]

Grant support: NIH research grants R01 DE 10742 and DE 14183 (D.K. Ann), and CA 94595 (Y. Chen); and Taiwan National Health Research Institutes grant MG-092-PP-03 (H.M. Shih). The imaging studies in this work were supported in part by NIH P30 DK48522 (Confocal Microscopy Subcore, University of Southern California Center for Liver Diseases).

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.

Note: X. Li and C. Clavijo contributed equally to this work.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/ 7/07; revised 11/28/07; accepted 2/15/08.