Abstract
Histone deacetylase (HDAC) plays a key role in gene expression, by suppressing the transcription of a number of target genes. Identification of such genes is important for deciphering the functional role of HDAC. Here, using cancer gene-focused DNA microarray analysis, we identified plakoglobin as a new target gene of HDAC. Functional inhibition of HDAC by its specific inhibitors induced the expression of plakoglobin by eight-fold in human fibrosarcoma HT1080 cells. However, the expression of beta-catenin, which is closely related to plakoglobin, was not altered, implying the specific function of HDAC in plakoglobin expression. Using antiacetyl-H4 antibody, chromatin immunoprecipitation analysis revealed that the distal region (-945 approximately -646) of the promoter of plakoglobin is responsible for the HDAC-mediated repression of the gene. Moreover, the induced expression of plakoglobin by the inhibition of HDAC activated the Tcf/Lef-dependent luciferase reporter gene, a well-known downstream effector of the Wnt signaling pathway. Furthermore, transient transfection of plakoglobin also activated Tcf/Lef reporter gene expression. Taken together, our results demonstrate that plakoglobin is a new target gene governed by HDAC, and that it acts as an oncogene in HT1080 cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Cell Line, Tumor
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Chromatin / drug effects
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Chromatin / genetics
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Chromatin / metabolism
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Chromatin Assembly and Disassembly / drug effects
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Cytoskeletal Proteins / genetics*
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / genetics
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Decitabine
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Desmoplakins
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Enzyme Inhibitors / pharmacology
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Fibrosarcoma / genetics*
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Fibrosarcoma / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic* / drug effects
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Genes, Reporter / genetics
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Histone Deacetylase Inhibitors
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / pharmacology
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Lymphoid Enhancer-Binding Factor 1
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Oligonucleotide Array Sequence Analysis
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Trans-Activators / genetics
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Transcription Factors / genetics
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Transcriptional Activation / drug effects
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beta Catenin
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gamma Catenin
Substances
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CTNNB1 protein, human
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Chromatin
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Desmoplakins
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Lymphoid Enhancer-Binding Factor 1
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RNA, Messenger
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Trans-Activators
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Transcription Factors
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beta Catenin
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gamma Catenin
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trichostatin A
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Decitabine
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Histone Deacetylases
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Azacitidine