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Molecular and Cellular Biology, March 2005, p. 1608-1619, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1608-1619.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Histone Deacetylase Inhibitors Down-Regulate bcl-2 Expression and Induce Apoptosis in t(14;18) Lymphomas

Hong Duan,1,2 Caroline A. Heckman,1,2 and Linda M. Boxer1,2*

Center for Molecular Biology in Medicine, Veterans Affairs, Palo Alto Health Care System, Palo Alto,1 Department of Medicine, Stanford University School of Medicine, Stanford, California2

Received 21 March 2004/ Returned for modification 27 April 2004/ Accepted 30 November 2004

Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBP{alpha} and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBP{alpha} binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas.

* Corresponding author. Mailing address: Hematology, CCSR 1155 269 Campus Dr., Stanford University School of Medicine, Stanford, CA 94305-5156. Phone: (650) 849-0551. Fax: (650) 858-3982. E-mail: lboxer{at}stanford.edu.

Molecular and Cellular Biology, March 2005, p. 1608-1619, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1608-1619.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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