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Molecular and Cellular Biology, June 2004, p. 5106-5118, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5106-5118.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activation of the Growth-Differentiation Factor 11 Gene by the Histone Deacetylase (HDAC) Inhibitor Trichostatin A and Repression by HDAC3

Xiaohong Zhang, Walker Wharton, Zhigang Yuan, Shih-Chang Tsai, Nancy Olashaw, and Edward Seto*

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

Received 5 November 2003/ Returned for modification 14 January 2004/ Accepted 23 February 2004

Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding growth-differentiation factor 11 (Gdf11), a transforming growth factor ß family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression.

* Corresponding author. Mailing address: H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612. Phone: (813) 979-6754. Fax: (813) 979-7264. E-mail: setoe{at}moffitt.usf.edu.

Molecular and Cellular Biology, June 2004, p. 5106-5118, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5106-5118.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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