PT - JOURNAL ARTICLE AU - Lu, Yunwei AU - Berenson, Anna AU - Lane, Ryan AU - Guelin, Isabelle AU - Li, Zhaorong AU - Chen, Yilin AU - Shah, Sakshi AU - Yin, Meimei AU - Soto-Ugaldi, Luis Fernando AU - Fiszbein, Ana AU - Fuxman Bass, Juan Ignacio TI - A large-scale cancer-specific protein–DNA interaction network AID - 10.26508/lsa.202402641 DP - 2024 Oct 01 TA - Life Science Alliance PG - e202402641 VI - 7 IP - 10 4099 - https://www.life-science-alliance.org/content/7/10/e202402641.short 4100 - https://www.life-science-alliance.org/content/7/10/e202402641.full SO - Life Sci. Alliance2024 Oct 01; 7 AB - Cancer development and progression are generally associated with gene dysregulation, often resulting from changes in the transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potential new therapeutics. This study presents a large-scale cancer gene TF-DNA interaction network, as well as an extensive promoter clone resource for future studies. Highly connected TFs bind to promoters of genes associated with either good or poor cancer prognosis, suggesting that strategies aimed at shifting gene expression balance between these two prognostic groups may be inherently complex. However, we identified potential for oncogene-targeted therapeutics, with half of the tested oncogenes being potentially repressed by influencing specific activators or bifunctional TFs. Finally, we investigate the role of intrinsically disordered regions within the key cancer-related TF ESR1 in DNA binding and transcriptional activity, and found that these regions can have complex trade-offs in TF function. Altogether, our study broadens our knowledge of the TFs involved in cancer gene regulation and provides a valuable resource for future studies and therapeutics.All data generated in this study are available within the article and its supplementary information.