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

Abstract

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 β 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.

We thank Ron Evans, Se-Jin Lee, Vicki Richon, Yang Shi, and Tso-Pang Yao for HDAC7 cDNA, mouse gdf11 cDNA, HDAC9 cDNA, pBS/U6, and HDAC10 cDNA, respectively; Anne Calof and Tere Antonia for discussion; and the Moffitt Cancer Center Core Facility for technical support.

This work was supported by grants to E.S. from the National Institutes of Health (GM58486 and GM64850) and the Kaul Foundation. X.Z. is a recipient of an American Cancer Society Institutional Grant.