https://ror.org/05qwgg493 Biology Department, Boston University, Boston, MA, USA.
https://ror.org/05qwgg493 Molecular Biology, Cellular Biology and Biochemistry Program, Boston University, Boston, MA, USA.
Life Sci Alliance. 2024 Jul 16;7(10). doi: 10.26508/lsa.202402641. Print 2024 Oct.
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.
癌症的发生和发展通常与基因失调有关，这通常是由于转录因子 (TF) 序列或表达的变化引起的。鉴定参与癌症基因调控的关键 TF 为潜在的新治疗方法提供了一个框架。本研究提出了一个大规模的癌症基因 TF-DNA 相互作用网络，以及一个用于未来研究的广泛的启动子克隆资源。高度连接的 TF 与与良好或不良癌症预后相关的基因的启动子结合，这表明旨在改变这两个预后组之间基因表达平衡的策略可能本质上很复杂。然而，我们确定了针对致癌基因的治疗方法的潜力，其中一半经过测试的致癌基因可能通过影响特定的激活剂或双功能 TF 被抑制。最后，我们研究了关键癌症相关 TF ESR1 中内在无序区域在 DNA 结合和转录活性中的作用，发现这些区域在 TF 功能中可能存在复杂的权衡。总的来说，我们的研究拓宽了我们对参与癌症基因调控的 TF 的认识，并为未来的研究和治疗提供了有价值的资源。
