A β-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Sporadic colorectal cancers are driven by APC mutations, leading to oncogenic β-catenin/TCF signaling.
• The GUCY2C receptor pathway, crucial for tumor suppression, is silenced early in tumorigenesis.
• Loss of GUCY2C ligands (guanylin, uroguanylin) is conserved in colorectal tumors, even with retained receptor.

Purpose of the Study:

• To investigate the mechanism by which β-catenin/TCF signaling silences GUCY2C ligand transcription.
• To identify specific genomic elements responsible for GUCY2C ligand repression.

Main Methods:

• RNA sequencing of colon cancer cell models with activated β-catenin/TCF signaling.
• Utilized luciferase reporters, ChIP sequencing, CRISPR/Cas9 knockout, and CRISPR epigenome editing.
• Cross-validated findings with human tissue ChIP sequencing data.

Main Results:

• GUCY2C hormones are highly sensitive targets repressed by β-catenin/TCF signaling.
• A novel locus control region upstream of the guanylin promoter mediates coordinated silencing of GUCY2C hormone genes.
• CRISPR epigenome editing at this locus restored GUCY2C ligand expression.

Conclusions:

• Identified DNA elements that corepress GUCY2C ligand transcription via β-catenin/TCF signaling, a novel step in tumorigenesis.
• Developed genomic strategies to reestablish GUCY2C hormone expression, potentially opposing cancer transformation.