This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fiskus, W. Articles by Bhalla, K. Search for Related Content PubMed PubMed Citation Articles by Fiskus, W. Articles by Bhalla, K.

Research Articles: Therapeutics, Targets, and Development

Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells

¹ Medical College of Georgia Cancer Center, Augusta, Georgia; ² Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; and ³ Novartis Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Kapil Bhalla, Medical College of Georgia Cancer Center, 1120 15th Street, CN2101A, Augusta, GA 30912. Phone: 706-721-0463; Fax: 706-721-0469. E-mail: kbhalla{at}mcg.edu

Abstract

Human enhancer of zeste 2 (EZH2) protein belongs to the multiprotein polycomb repressive complex 2, which also includes suppressor of zeste 12 (SUZ12) and embryonic ectoderm development (EED). The polycomb repressive complex 2 complex possesses histone methyltransferase activity mediated by the Su(var)3-9, enhancer of zeste, and trithorax domain of EZH2, which methylates histone H3 on lysine (K)-27 (H3K27). In the present studies, we determined that treatment with the hydroxamate histone deacetylase inhibitor LBH589 or LAQ824 depleted the protein levels of EZH2, SUZ12, and EED in the cultured (K562, U937, and HL-60) and primary human acute leukemia cells. This was associated with decreased levels of trimethylated and dimethylated H3K27, with concomitant depletion of the homeobox domain containing HOXA9 and of MEIS1 transcription factors. Knockdown of EZH2 by EZH2 small interfering RNA also depleted SUZ12 and EED, inhibited histone methyltransferase activity, and reduced trimethylated and dimethylated H3K27 levels, with a concomitant loss of clonogenic survival of the cultured acute myelogenous leukemia (AML) cells. EZH2 small interfering RNA sensitized the AML cells to LBH589-mediated depletion of EZH2, SUZ12, and EED; loss of clonogenic survival; and LBH589-induced differentiation of the AML cells. These findings support the rationale to test anti-EZH2 treatment combined with hydroxamate histone deacetylase inhibitors as an antileukemia epigenetic therapy, especially against AML with coexpression of EZH2, HOXA9, and MEIS1 genes. [Mol Cancer Ther 2006;5(12):3096–104]

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.

Received 7/18/06; revised 9/12/06; accepted 10/30/06.

This article has been cited by other articles:

				R. Rao, W. Fiskus, Y. Yang, P. Lee, R. Joshi, P. Fernandez, A. Mandawat, P. Atadja, J. E. Bradner, and K. Bhalla HDAC6 inhibition enhances 17-AAG-mediated abrogation of hsp90 chaperone function in human leukemia cells Blood, September 1, 2008; 112(5): 1886 - 1893. [Abstract] [Full Text] [PDF]

				J. M. Lubieniecka, D. R.H. de Bruijn, L. Su, A. H.A. van Dijk, S. Subramanian, M. van de Rijn, N. Poulin, A. G. van Kessel, and T. O. Nielsen Histone Deacetylase Inhibitors Reverse SS18-SSX-Mediated Polycomb Silencing of the Tumor Suppressor Early Growth Response 1 in Synovial Sarcoma Cancer Res., June 1, 2008; 68(11): 4303 - 4310. [Abstract] [Full Text] [PDF]

				V. K. Rajasekhar and M. Begemann Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell Perspective Stem Cells, October 1, 2007; 25(10): 2498 - 2510. [Abstract] [Full Text] [PDF]