Abstract
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.
Highlights
DOC-2/DAB2, originally isolated as a potential tumor suppressor gene from human ovarian carcinoma [1], is a phosphoprotein involved in modulating multiple signaling pathways [2,3,4,5] and protein trafficking [6]
It seems that DOC-2/DAB2 plays a critical role in the development of visceral endoderm during mouse embryogenesis [19, 26]
The DA and DB exhibited higher activity induced by GATA6 than DC (Fig. 3B) and the binding of GATA6 to those consensus sequence was observed (Fig. 5C ), indicating that GATA6 is a potent transcription factor in modulating DOC-2/DAB2 gene expression in transitional cell carcinoma (TCC) cells
Summary
DOC-2/DAB2, originally isolated as a potential tumor suppressor gene from human ovarian carcinoma [1], is a phosphoprotein involved in modulating multiple signaling pathways [2,3,4,5] and protein trafficking [6]. Decreased expression of DOC-2/DAB2 has been observed in several cancers [7,8,9,10], including prostate, mammary, colon, and choriocarcinoma. The underlying mechanism leading to the down-regulation of DOC-2/DAB2 gene expression is largely unknown. Data from Fulop et al [10] and our previous study [7] showed that an increased expression of DOC-2/DAB2 can suppress the growth of choriocarcinoma and prostate cancer cells. These data indicate the tumor suppressive role of DOC-2/DAB2 in cancer development. To understand the regulation of DOC-2/DAB2 gene, we recently showed that the increased promoter activity of DOC-2/DAB2
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