PDF(Pubmed)
Abstract：
The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of how the functional crosstalk between the antagonist and the β-catenin/CBP interaction affects changes in 3D chromatin architecture and, thereby, gene expression and downstream effects remains to be elucidated. Here, we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate that the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1-a key insulin signaling gene-significantly impeding pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
摘要：
靶向β-连环蛋白/CBP相互作用的治疗潜力已在各种临床前肿瘤模型中被证明与小分子抑制剂，ICG-001,特征为β-连环蛋白/CBP拮抗剂。尽管ICG-001对CBP的N端具有高结合特异性，这种β-连环蛋白/CBP拮抗剂表现出多效作用。我们最近的研究发现，响应胰腺癌细胞中β-连环蛋白/CBP相互作用的破坏，三维（3D）染色质结构的整体变化。然而,了解拮抗剂与β-catenin/CBP相互作用之间的功能串扰如何影响3D染色质结构的变化，因此，基因表达和下游效应仍有待阐明。这里,我们对ICG-001治疗前后的典型和患者来源的胰腺癌细胞进行了Hi-C分析.除了3D染色质结构域的整体改变，我们意外地发现了富含改变的染色质结构域的胰岛素信号基因。我们进一步证明，与胰岛素信号基因相关的染色质环在ICG-001治疗后显著减弱。我们最终引发了IRS1-一个关键的胰岛素信号基因循环的缺失，显著阻碍了胰腺癌细胞的生长，这表明循环介导的胰岛素信号可能是促进胰腺癌进展的致癌途径。我们的工作表明，靶向胰腺癌中异常胰岛素染色质循环可能提供治疗益处。
