The role of putative promoter regions in regulation of conserved interferon and oxidative stress gene expression signatures in cancer

Oxidative stress (OS) and interferon (IFN) related gene expression signatures are found in most transcriptome profiling studies of carcinomas. A subset of the genes in these signatures occurs in multiple tumor profiling studies and appears to be constitutively over expressed in certain NCI-60 cell lines. The constitutive over expression of stress pathways in a subset of NCI-60 cell lines grown under unperturbed conditions and tumor samples suggests that these pathways may be aberrantly regulated in these lines and tumors. We used transient transfection reporter assay and various computational approaches to assess the role of cis-acting DNA sequences in regulating the coexpression of conserved OS and IFN gene expression signatures. To explore the degree to which promoter activity alone can account for variation in expression of the conserved expression signatures, we measured the activity of -1000 bp to +200 bp fragments relative to transcription start site (TSS) for 87 genes in 58 cell lines. Analysis of the correlation between steady state gene expression from the endogenous genes in these cells and promoter activity measured by the transient transfection assay in each cell line showed that the promoter activities for OS and IFN regulated genes are better correlated to steady state gene expression levels compared to random controls. This suggests a larger role for promoter activity in determining message level for genes participating in recurrent expression signatures as compared to random genes. Apparent physiological regulation of promoter activity was evident from cluster analysis on promoter activity patterns across the cell lines. Computational analysis of the selected 1200 bp promoter regions identified NFKB, IKZF, IRF1, IRF2, v-Maf transcription factors as potential regulatory elements for the studied IFN genes. Similarly, SBF1, HNF1, SREBP1 and NRF2 binding sites are predicted as regulatory elements for conserved OS genes. This analysis suggests a role for promoter activity patterns in better identification of the regulatory networks that can possibly help dissect aberrantly regulated pathways in cancer.