3D Chromatin Alteration by Disrupting β-Catenin/CBP Interaction Is Enriched with Insulin Signaling in Pancreatic Cancer. Cancers (Basel) 2024 Jun 12;16(12)
Date
06/27/2024Pubmed ID
38927910Pubmed Central ID
PMC11201718DOI
10.3390/cancers16122202Scopus ID
2-s2.0-85197122887 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
Author List
Zhou Y, He Z, Li T, Choppavarapu L, Hu X, Cao R, Leone GW, Kahn M, Jin VXAuthors
Lavanya Choppavarapu PhD Research Scientist I in the Data Science Institute department at Medical College of WisconsinVictor X. Jin PhD Professor in the Data Science Institute department at Medical College of Wisconsin
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Pathology department at Medical College of Wisconsin
