Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3.
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 beta 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.
Zhang
Xiaohong
X
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Wharton
Walker
W
Yuan
Zhigang
Z
Tsai
Shih-Chang
SC
Olashaw
Nancy
N
Seto
Edward
E
D000107:Acetylation; D000818:Animals; D041702:BALB 3T3 Cells; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D055412:Growth Differentiation Factors; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000099186:Histone Deacetylase 3
D019485:Bone Morphogenetic Proteins; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D055412:Growth Differentiation Factors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D006877:Hydroxamic Acids; D008239:Lysine; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000099186:Histone Deacetylase 3; C492266:GDF11 protein, human; C119153:Gdf11 protein, mouse; C012589:trichostatin A