Comparative Promoter Analysis of Doxorubicin Resistance-associated Genes Suggests E47 as a Key Regulatory Element

Working under the assumption that up- or down-regulation of genes implicated in chemoresistance may be the result of altered function of regulatory transcription factors (TF), over-represented TF-binding sites of gene lists previously associated with doxorubicin resistance were the target of our search. First, a data warehouse was set up containing 52 genes which were present in at least two gene lists; of those, proximal promoter sequences (1 kb upstream and 0.05 kb downstream of the transcriptional start sites) could be retrieved from genomic databases for 45 genes using the EZ-Retrieve. The TOUCAN tool MotifScanner, which searches the TRANSFAC database, was used to detect TF-binding sites (TFBSs) in our set of sequences. The statistics tool of the Java program TOUCAN was applied to the data with the appropriate expected frequencies file to compare the measured prevalence to a background model. The most significantly over-represented TFBS was that of E47 (p=0.00024, prevalence: 0.2 vs. background: 8.19E-6). In summary, based on the results of our analysis it is hypothesized that the E47 transcription factor may contribute to doxorubicin resistance.