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3D Chromatin Alteration by Disrupting β-Catenin/CBP Interaction Is Enriched with Insulin Signaling in Pancreatic
Yufan Zhou1, Zhijing He1,2, Tian Li1
1Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
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.
Insights
Targeting the β-catenin/CBP interaction with ICG-001 alters pancreatic cancer cell 3D chromatin architecture. This disruption weakens insulin signaling, impeding cancer growth and suggesting new therapeutic strategies.
Area of Science:
- Cancer Biology
- Epigenetics
- Molecular Oncology
Background:
- The β-catenin/CBP interaction is a therapeutic target in cancer, with ICG-001 as a known antagonist.
- ICG-001 exhibits pleiotropic effects beyond its specific binding to CBP.
- Previous studies indicated ICG-001 induces global 3D chromatin architecture changes in pancreatic cancer cells.
Purpose of the Study:
- To investigate the functional crosstalk between ICG-001, β-catenin/CBP interaction, and 3D chromatin architecture in pancreatic cancer.
- To elucidate how these interactions affect gene expression and downstream cellular effects.
- To identify potential therapeutic benefits of targeting aberrant insulin chromatin looping.
Main Methods:
- Hi-C analyses were performed on pancreatic cancer cells (canonical and patient-derived) before and after ICG-001 treatment.
- Global 3D chromatin architecture alterations were assessed.
- Chromatin loops associated with insulin signaling genes were specifically examined.
Main Results:
- ICG-001 treatment caused global alterations in 3D chromatin domains.
- Insulin signaling genes were found to be enriched in these altered chromatin domains.
- Chromatin loops involving key insulin signaling genes, such as IRS1, were significantly weakened, impeding cancer cell growth.
Conclusions:
- Disruption of the β-catenin/CBP interaction by ICG-001 impacts 3D chromatin architecture and insulin signaling in pancreatic cancer.
- Looping-mediated insulin signaling acts as an oncogenic pathway promoting pancreatic cancer progression.
- Targeting aberrant insulin chromatin looping presents a potential therapeutic strategy for pancreatic cancer.
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