Requirement of a specific Sp1 site for histone deacetylase-mediated repression of transforming growth factor beta Type II receptor expression in human pancreatic cancer cells

Shujie Zhao, Kolaparthi Venkatasubbarao, Senlin Li, James W Freeman
Cancer Research 2003 May 15, 63 (10): 2624-30
In this study, we demonstrate a novel mechanism by which down-regulation of transforming growth factor beta type II receptor (TbetaRII) 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 TbetaRII promoter activity and induces TbetaRII expression. The transcriptional activation of TbetaRII 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 TbetaRII 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 TbetaRII 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 TbetaRII 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 TbetaRII. This study further suggests that the specificity of this Sp1 site for HDAC-mediated repression of TbetaRII 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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