Synergistic induction of DOC-2/DAB2 gene expression in transitional cell carcinoma in the presence of GATA6 and histone deacetylase inhibitor.
The down-regulation of DOC-2/DAB2 gene, which encodes a unique phosphoprotein modulating signal pathways elicited by exogenous stimuli, is often associated with several cancer types; however, the underlying mechanism is still unknown. Dramatically different expression levels of DOC-2/DAB2 mRNA and protein are observed among several human transitional cell carcinoma (TCC) cell lines, suggesting that transcriptional regulation may play a role in these cells. In this study, we have shown that the histone acetylation status associated with the 5' upstream regulatory sequence of DOC-2/DAB2 gene is one of the key determinants for its gene expression. In addition, GATA6 but not other GATA family members, such as GATA2 and GATA4, can specifically induce DOC-2/DAB2 promoter activity, although GATA transcription factors share a very similar DNA-binding sequence. We also show that increased histone acetylation and the presence of GATA6 have a synergistic effect on DOC-2/DAB2 promoter activity, which results in the elevation of DOC-2/DAB2 protein expression. Thus, we conclude that transcriptional regulation of DOC-2/DAB2 gene in human TCC is determined by histone acetylation and a specific transcription factor (i.e., GATA6), which underlie the reduced DOC-2/DAB2 protein expression in TCC cells.
Zhou
Jian
J
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA.
Hernandez
Gina
G
Tu
Szu-Wei
SW
Scholes
Jessica
J
Chen
Hong
H
Tseng
Ching-Ping
CP
Hsieh
Jer-Tsong
JT
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002295:Carcinoma, Transitional Cell / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology; D015536:Down-Regulation; D050993:GATA6 Transcription Factor; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D002843:Chromatin; C102885:DAB2 protein, human; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C087123:romidepsin; D006655:Histone Deacetylases