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.

Cancer is increasingly recognized as a disease of transcriptional dysregulation in which genetic alterations and epigenetic remodeling cooperate to reprogram gene regulatory networks that govern cellular identity, proliferation, differentiation, and therapeutic response. Enhancer–promoter interactions are an important component of the regulatory systems that establish cell-type-specific gene expression and lineage identity. Cancer cells exploit the intrinsic plasticity of the epigenome to remodel enhancer landscapes, redistribute lineage-specific transcription factors (TFs), alter chromatin accessibility, reorganize three-dimensional (3D) genome architecture, and establish novel enhancer–promoter interactions that sustain oncogenic transcriptional programs. In this review, we discuss how enhancer–promoter communication is established and maintained within the 3D genome and examine the molecular mechanisms and drivers underlying epigenetic rewiring of enhancer–promoter interactions in cancer. We also highlight how the alterations of these epigenetic processes contribute to cancer initiation, progression, metastasis, and therapeutic resistance. Finally, we discuss epigenetic therapeutic strategies and emerging genomic technologies that exploit aberrant enhancer–promoter interactions to advance precision oncology.

Here, we present an optimized high-resolution Hi-C protocol for human breast tissues using the Phase Genomics Proximo Hi-C Kit. We describe steps for liquid nitrogen tissue processing, crosslinking, and quenching, followed by cell lysis and controlled chromatin fragmentation. Proximity ligation captures three-dimensional interactions, followed by reverse crosslinking, DNA purification, and streptavidin bead enrichment. Libraries are prepared on beads, amplified, and cleaned with size selection, producing high-quality material for Illumina sequencing and genome-wide 3D chromatin analysis. For complete details on the use and execution of this protocol, please refer to Choppavarapu et al.¹.