Synergistic induction of DOC-2/DAB2 gene expression in transitional cell carcinoma in the presence of GATA6 and histone deacetylase inhibitor.
Synergistic induction of DOC-2/DAB2 gene expression in transitional cell carcinoma in the presence of GATA6 and histone deacetylase inhibitor.
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GATA6 和组蛋白脱乙酰酶抑制剂存在下协同诱导移行细胞癌中的 DOC-2/DAB2 基因表达。
DOI：
10.1158/0008-5472.can-04-3672
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发表时间：
2005
期刊：
影响因子：
11.2
通讯作者：
Hsieh,Jer-Tsong
中科院分区：
文献类型：
--
作者：
Zhou,Jian;Hernandez,Gina;Tu,Szu-Wei;Scholes,Jessica;Chen,Hong;Tseng,Ching-Ping;Hsieh,Jer-Tsong
DOC-2/DAB 2基因编码一种独特的磷蛋白，可调节外源性刺激引起的信号通路，其下调常与多种肿瘤相关，但其机制尚不清楚。DOC-2/DAB 2 mRNA和蛋白在几种人移行细胞癌（TCC）细胞系中的表达水平存在显著差异，提示转录调控可能在这些细胞中起作用。本研究表明，DOC-2/DAB 2基因5′上游调控序列的组蛋白乙酰化状态是其基因表达的关键决定因素之一。此外，GATA 6而不是其他加塔家族成员，如GATA 2和GATA 4，可以特异性地诱导DOC-2/DAB 2启动子活性，尽管加塔转录因子共享非常相似的DNA结合序列。我们还发现，增加组蛋白乙酰化和GATA 6的存在对DOC-2/DAB 2启动子活性具有协同作用，从而导致DOC-2/DAB 2蛋白表达的升高。因此，我们的结论是DOC-2/DAB 2基因在人膀胱移行细胞癌中的转录调控是由组蛋白乙酰化和一个特异性转录因子（即，GATA 6），这是TCC细胞中DOC-2/DAB 2蛋白表达降低的基础。
The down-regulation ofDOC-2/DAB2gene, 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 ofDOC-2/DAB2gene 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 induceDOC-2/DAB2promoter 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 onDOC-2/DAB2promoter activity, which results in the elevation of DOC-2/DAB2 protein expression. Thus, we conclude that transcriptional regulation ofDOC-2/DAB2gene 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.