A large-scale cancer-specific protein-DNA interaction network

Cancer development and progression are generally associated with dysregulation in gene expression, often resulting from changes in transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potentially new cancer therapeutics. This study presents a large-scale TF-centered cancer gene TF-DNA interaction network as well as a comprehensive promoter clone resource for mechanistic studies. Using enhanced yeast one-hybrid (eY1H) and paired yeast one-hybrid (pY1H) assays, we identified 1,218 interactions between 265 TFs and the promoter of 108 cancer-related genes. Our findings indicate that most highly connected TFs, or 'hubs', do not show a preference for binding to promoters of genes with either good or poor cancer prognosis. This suggests that strategies aimed at shifting gene expression balance between these two prognostic groups may be inherently complex. However, we identified potential for targeted therapeutic intervention, with half of the tested oncogenes potentially modifiable by influencing specific activator or bifunctional TFs. Finally, we leverage our clone resource to study the role of intrinsically disordered regions within TFs, particularly ESR1, on DNA binding and transcriptional activity, and found that these regions can have complex trade-offs in TF function. Overall, our study not only broadens our understanding of cancer gene regulation but also provides a valuable resource for future studies, laying a foundation for potential therapeutic strategies targeting TFs in cancer.