3D Chromatin Alteration by Disrupting β-Catenin/CBP Interaction Is Enriched with Insulin Signaling in Pancreatic Cancer

Author:

Zhou Yufan1,He Zhijing12,Li Tian1,Choppavarapu Lavanya345,Hu Xiaohui6,Cao Ruifeng7ORCID,Leone Gustavo W.48,Kahn Michael9ORCID,Jin Victor X.345ORCID

Affiliation:

1. Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA

2. Department of Stomatology, The Second Xiangya Hospital of Central South University, Changsha 410011, China

3. Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA

4. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA

5. Mellowes Center for Genomic Sciences and Precision Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA

6. Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China

7. Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, The State University of New Jersey, Piscataway, NJ 08854, USA

8. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA

9. Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, 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.

Funder

National Institutes of Health

Publisher

MDPI AG

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