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.
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.
Park
Seok Hee
SH
Laboratory of Cell Regulation and Carcinogenesis, the Developmental Therapeutics Program, and the Medicine Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lee
Sae Ra
SR
Kim
Byung Chul
BC
Cho
Eun Ah
EA
Patel
Sejal P
SP
Kang
Hee-Bum
HB
Sausville
Edward A
EA
Nakanishi
Osamu
O
Trepel
Jane B
JB
Lee
Byoung Ick
BI
Kim
Seong-Jin
SJ
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
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