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.
靶向β-catenin/CBP相互作用的治疗潜力已在多种临床前肿瘤模型中得到证实，其中小分子抑制剂ICG-001作为β-catenin/CBP拮抗剂发挥关键作用。尽管ICG-001对CBP氨基末端具有高结合特异性，但该拮抗剂表现出多效性作用。我们近期研究发现，胰腺癌细胞中β-catenin/CBP相互作用被破坏会导致三维染色质结构的全局性改变。然而，关于拮抗剂与β-catenin/CBP相互作用之间的功能互作如何影响三维染色质结构变化，进而调控基因表达及下游效应，其机制仍有待阐明。本研究通过Hi-C技术分析了经典及患者来源的胰腺癌细胞在ICG-001处理前后的染色质空间构象。除观察到三维染色质结构域的全局性改变外，我们意外发现改变的结构域中富集了胰岛素信号通路相关基因。进一步研究表明，ICG-001处理后与胰岛素信号基因相关的染色质环结构显著减弱。最终我们证实，关键胰岛素信号基因IRS1的染色质环缺失能显著抑制胰腺癌细胞生长，表明环介导的胰岛素信号通路可能作为促癌通路驱动胰腺癌进展。本研究表明，靶向胰腺癌中异常的胰岛素染色质环结构可能具有治疗价值。
肿瘤(癌症)患者之家