Regulatory mechanisms controlling human E-cadherin gene expression

Abstract

In cancer cells, loss of E-cadherin gene expression caused dysfunction of the cell-cell junction system, triggering cancer invasion and metastasis. Therefore, E-cadherin is an important tumor-suppressor gene. To understand how E-cadherin gene expression is regulated in cancer cells, we have used E-cadherin-positive and -negative expressing cells to find out the possible up-or downregulating transcription factors in human E-cadherin regulatory sequences. Functional analysis of human E-cadherin regulatory sequences constructs indicated that AML1, Sp1, and p300 may play important roles in promoting E-cadherin expression. In addition, we found there are four HNF3-binding sites in human E-cadherin regulatory sequences. The exogenous HNF3 can enhance the E-cadherin promoter activity in metastatic breast cancer cells and the metastatic breast cancer cells stably transfected with HNF3 showed re-expression of E-cadherin. The HNF3 stable transfectants changed from mesenchymal-like into epithelial morphology. The transwell assays showed the re-expressed E-cadherin reduced cell motility of metastatic breast cancer cells. These results suggested HNF3 may play important roles in the upregulation of the E-cadherin promoter, with the consequent re-expression of E-cadherin, thus reducing the metastatic potential of breast cancer cells. These findings suggested HNF3 plays important roles in the upregulation of the E-cadherin gene and may be able to reduce the motility of metastatic breast cancer cells.

The miR-106b∼25 cluster promotes bypass of doxorubicin-induced senescence and increase in motility and invasion by targeting the E-cadherin transcriptional activator EP300

“…Bioinformatic analysis to predict targets of the miR106bB25 cluster 39 identified individual single sites for both mir-106b/93 and mir-25 in the 3 0 -UTR of EP300. As EP300 has been identified as a positive regulator of E-cadherin (CDH1) gene expression, 40 we hypothesized that a negative correlation should exist between the miR-106bB25 cluster and EP300 expression. Indeed, drug-resistant MD60 cells, which overexpress the miR-106bB25 cluster (Figure 1d), showed reduced EP300 and CDH1, but increased VIM (encoding vimentin, a mesenchymal intermediate filament protein activated during EMT 4 ) mRNA levels (Figure 6a).…”

Specificity Protein 1 (Sp1) Maintains Basal Epithelial Expression of the miR-200 Family

“…We show that Sp1 maintains basal miR-200 expression in both epithelial and mesenchymal cells, but in mesenchymal cells this capacity is likely overruled by competition with transcriptional repressors such as ZEB. In addition to miR-200, Sp1 has previously been shown to be an important transcriptional activator of E-cadherin (45), with re-expression of Sp1 increasing E-cadherin levels and suppressing metastasis in a lung adenocarcinoma model (46). Thus, Sp1 may promote an epithelial state by activating the expression of several key epithelial enforcing genes.…”

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

“…Altered expression of these transcription factors seems to be also associated with an altered overexpression of transcriptional repressors of E-cadherin in tumour cells (Batlle et al, 2000;Cano et al, 2000;Comijn et al, 2001;Hajra et al, 2002;Yang et al, 2004;Eger et al, 2005). CDH1 gene expression is upregulated by several factors, AML1, p300 and HNF3 (Liu et al, 2005). Also post-transcriptional regulation of E-cadherin has been observed and recently ADAM10 was identified as the cleaving protease (Maretzky et al, 2005).…”