Transcriptional Regulation of RKIP in Prostate Cancer Progression
Raf Kinase Inhibitor Protein (RKIP), a negative regulator of the Raf/MEK/ERK and NF-?B signaling pathways, is downregulated in several cancers, including prostate cancer. RKIP expression is further diminished in metastatic prostate cancer, qualifying it as a metastasis suppressor gene. The transcriptional regulation of RKIP in prostate cancer is unknown; however, promoter studies suggest that methylation is not the means of transcriptional inhibition.
The decrease in RKIP at the time of metastatic invasion suggests that factors involved in the epithelial-to-mesenchymal transition (EMT) may be involved in its regulation. The Snail superfamily of transcription factors are involved in the EMT process in normal development and in cancer. Protein levels of Snail were low in the low-mestastatic prostate cancer cell line LNCaP and increased in the PC3 and Du145 cell lines derived from metastases of prostate adenocarcinoma. The endogenous protein levels of E-cadherin, a known target of Snail repression, and RKIP were higher in LNCaP cells and diminished in PC3 and Du145 cells. Overexpressing Snail in LNCaP cells resulted in diminished RKIP levels, and knocking down Snail in PC3 and Du145 cells increased RKIP expression. RKIP promoter activity was repressed by both Snail and Slug. Chromatin immunoprecipitation assays showed that Snail associates with E-box elements near the RKIP transcriptional start site.
We identify a physiological relationship between RKIP and Snail in prostate cancer through analysis of publicly available microarray data. There is a significant
negative correlation between RKIP and Snail, Snail and E-cadherin, and also RKIP and EZH2, but not RKIP and Slug. Finally, hierarchical cluster analysis was used to attempt to determine the expression profile to which RKIP and Snail belong and to predict genes that may be involved in the regulation of RKIP.
School:University of Toledo Health Science Campus
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:rkip snail slug prostate cancer metastasis pebp microarray database
Date of Publication:01/01/2008