Abstract
Loss of E-cadherin is one of the key steps in tumor progression. Our previous studies demonstrate that SAM pointed domain-containing ETS transcription factor (SPDEF) inhibited prostate cancer metastasis in vitro and in vivo. In the present study, we evaluated the relationship between SPDEF and E-cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor cell invasion and metastasis. The results presented here demonstrate a direct correlation between expression of E-cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that modulation of E-cadherin and SPDEF had similar effects on cell migration/invasion. In addition, siRNA-mediated knockdown of E-cadherin was sufficient to block the effects of SPDEF on cell migration and invasion. We also show that stable forced expression of SPDEF results in increased expression of E-cadherin, whereas down-regulation of SPDEF decreased E-cadherin expression. In addition, we demonstrate that SPDEF expression is not regulated by E-cadherin. Moreover, our chromatin immunoprecipitation and luciferase reporter assay revealed that SPDEF occupies E-cadherin promoter site and acts as a direct transcriptional inducer of E-cadherin in prostate cancer cells. Taken together, to the best of our knowledge, these studies are the first demonstrating requirement of SPDEF for expression of E-cadherin, an essential epithelial cell junction protein. Given that loss of E-cadherin is a central tenant in tumor metastasis, the results of our studies, by providing a new mechanism for regulation of E-cadherin expression, could have far reaching impact.
Highlights
SAM pointed domain-containing ETS transcription factor (SPDEF) functions like a tumor metastasis suppressor
Loss of SPDEF Is Associated with Loss of E-cadherin in Prostate Cancer—First, we investigated the correlation between SPDEF and E-cadherin mRNA expression levels in different prostate cancer cell lines by quantitative real time RT-PCR on a panel of immortalized prostate cancer cell lines (LNCaP, LNCaP C4-2, LNCaP C4-2B, and PC3) with varying degrees of tumorigenic and metastatic potential to compare expression levels of SPDEF and E-cadherin with respect to nontumorigenic human prostate epithelial cells, RWPE-1
In the current study we have discovered that, in prostate cancer cells, the loss of SPDEF is associated with loss of E-cadherin
Summary
SPDEF functions like a tumor metastasis suppressor. the underlying mechanism remains unclear. We evaluated the relationship between SPDEF and E-cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor cell invasion and metastasis. Given that loss of E-cadherin is a central tenant in tumor metastasis, the results of our studies, by providing a new mechanism for regulation of E-cadherin expression, could have far reaching impact. Because loss of SPDEF and E-cadherin has been observed in cancer progression in several independent studies as described above, we set out to determine whether or not there existed any association between expression of SPDEF and E-cadherin in prostate cancer cells. Our results provide the first direct demonstration of regulation of E-cadherin expression and a critical role for E-cadherin in modulating the function of SPDEF with respect to cell migration and invasion in prostate cancer
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