title: Transcriptional regulation of the transforming growth factor beta type II receptor gene by histone acetyltransferase and deacetylase is mediated by NF-Y in human breast cancer cells.
abstract: Transcriptional repression of the transforming growth factor-beta (TGF-beta) type II receptor (TbetaRII) gene is one of several mechanisms leading to TGF-beta resistance. Previously, we have shown that MS-275, a synthetic inhibitor of histone deacetylase (HDAC), specifically induces the expression of the TbetaRII gene and restores the TGF-beta signaling in human breast cancer cell lines. However, little is known about the mechanism by which inhibition of HDAC activates TbetaRII expression. MS-275 treatment of cells expressing a wild-type TbetaRII promoter/luciferase construct resulted in a 10-fold induction of the promoter activity. DNA transfection and an electrophoretic mobility shift assay showed that the induction of the TbetaRII promoter by MS-275 requires the inverted CCAAT box and its cognate binding protein, NF-Y. In addition, a DNA affinity pull-down assay indicated that the PCAF protein, a transcriptional coactivator with intrinsic histone acetyltransferase (HAT) activity, is specifically recruited to the NF-Y complex in the presence of either MS-275 or trichostatin A. Based on these results, we suggest that treatment with the HDAC inhibitor induces TbetaRII promoter activity by the recruitment of the PCAF protein to the NF-Y complex, interacting with the inverted CCAAT box in the TbetaRII promoter.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, the Developmental Therapeutics Program, and the Medicine Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Sae Ra
authors.initials: SR
authors.lastname: Lee
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Kim
authors.forename: Eun Ah
authors.initials: EA
authors.lastname: Cho
authors.forename: Sejal P
authors.initials: SP
authors.lastname: Patel
authors.forename: Hee-Bum
authors.initials: HB
authors.lastname: Kang
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakanishi
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Byoung Ick
authors.initials: BI
authors.lastname: Lee
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism*; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology*; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines / Q000494:pharmacology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D023081:CCAAT-Binding Factor; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; D018125:Receptors, Transforming Growth Factor beta; D029701:Saccharomyces cerevisiae Proteins; C118739:entinostat; C012589:trichostatin A; D004247:DNA; D008156:Luciferases; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D006655:Histone Deacetylases