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Molecular Biology and Genetics |
Department of Medicine, Division of Medical Oncology, University of Texas Health Science Center, San Antonio, Texas 78229-3900
In this study, we demonstrate a novel mechanism by which down-regulation of transforming growth factor ß type II receptor (TßRII) is mediated by a histone deacetylase (HDAC) in pancreatic ductal adenocarcinoma (PDAC) cells. Treatment of PDAC cell lines BxPC-3 and MIA PaCa-2 with a specific HDAC inhibitor, trichostatin A (TSA), strongly activates TßRII promoter activity and induces TßRII expression. The transcriptional activation of TßRII by TSA was correlated with a decrease in HDAC activity and an increase in acetylated histone H4 protein. Correspondingly, an increase in the association of TßRII promoter with acetylated histone H4 was detected in the TSA-treated cells as determined by a chromatin immunoprecipitation assay. We found that a specific Sp1 site (Sp1C, located at -102 bp relative to the transcription start site) adjacent to an inverted CCAAT box (-83 bp) is required for TSA-mediated activation of the TßRII promoter. Furthermore, we determined that HDAC1 complexed with Sp1 in PDAC cells and that TSA treatment interfered with this association. Diminished binding of HDAC1 to the -112 to -65 bp region of the TßRII promoter after TSA treatment was confirmed by a DNA affinity precipitation assay. This is the first study to demonstrate the requirement of a specific Sp1 site for TSA-mediated transcriptional activation of TßRII. This study further suggests that the specificity of this Sp1 site for HDAC-mediated repression of TßRII may involve the interaction of the Sp1-HDAC1 complex with components of the cognate transcriptional regulators that bind to the inverted CCAAT box.
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