Abstract
ETS is a family of transcriptional regulators with functions in most biological processes. Dysregulated ETS factor function leads to altered expression of multiple genes that play critical roles in many of the processes required for cancer progression. While the Ets family gene, prostate-derived ETS factor (PDEF), is expressed in epithelial tissues including prostate, breast, and colon, PDEF protein expression has been found to be reduced or lost during prostate and breast cancer progression. The goal of this study was to examine the expression and biologic impact of altered PDEF expression in colon cancer. PDEF mRNA and protein are not detectable in several colon-cancer-derived cell lines. Re-expression of PDEF in colon cancer cells inhibits growth and migration. Growth affects are due to altered cellular proliferation, indicated by increased altered cell population in G(1) and S phases of the cell cycle, as well as increased apoptosis. Relevant to its modulation of growth and migration phenotypes, PDEF expression resulted in altered expression of genes with established roles in cell cycle, motility, and invasion. Furthermore, chromatin immunoprecipitation studies show that p21 and urokinase plasminogen activator (uPA) are direct PDEF transcriptional targets. While non-tumor colon epithelium expresses PDEF mRNA and protein, the majority of tumors showed decreased mRNA and/or protein expression. In human tumor tissue samples, PDEF expression was inversely correlated with the expression levels of uPA. Collectively, the data support the model that PDEF is a negative regulator of tumor progression by modulating the expression of growth and migration promoting genes.