ArticleCellular and molecular gastroenterology and hepatology2022
A β-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer.
Article in Cellular and molecular gastroenterology and hepatology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it, 12 citations in OpenAlex.
- Guanylate cyclase-C Signaling Axis as a theragnostic target in colorectal cancer: a systematic review of literature.Frontiers in oncology · 2023Pooled it
- Targeting molecular and genetic pathways driving tumorigenesis for precision therapy in colorectal cancer.Cancer biology & therapy · 2026Review
- MUC1-Driven Guanylin Gene Delivery via Succinylated PEI-9 Nanocarrier for Colorectal Cancer Treatment: An in Silico and In vitro Study.Advanced pharmaceutical bulletin · 2025Article
- Functional genomic profiling of O-GlcNAc reveals its context-specific interplay with RNA polymerase II.Genome biology · 2025Article
- Gene Coexpression and miRNA Regulation: A Path to Early Intervention in Colorectal Cancer.Human gene therapy · 2024Article
- Application of CRISPR-Cas9 gene editing technology in basic research, diagnosis and treatment of colon cancer.Frontiers in endocrinology · 2023Review
- Effect of guanylin peptides on pancreas steatosis and function in experimental diet-induced obesity and after bariatric surgery.Frontiers in endocrinology · 2023Article
- Guanylyl cyclase C as a diagnostic and therapeutic target in colorectal cancer.Personalized medicine · 2022Review
- Cordycepin Suppresses The Malignant Phenotypes of Colon Cancer Cells through The GSK3ß/ß-catenin/cyclin D1 Signaling Pathway.Cell journal · 2022Article
- Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities.Frontiers in endocrinology · 2022Review
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
BACKGROUND &
aimsSporadic colorectal cancers arise from initiating mutations in APC, producing oncogenic β-catenin/TCF-dependent transcriptional reprogramming. Similarly, the tumor suppressor axis regulated by the intestinal epithelial receptor GUCY2C is among the earliest pathways silenced in tumorigenesis. Retention of the receptor, but loss of its paracrine ligands, guanylin and uroguanylin, is an evolutionarily conserved feature of colorectal tumors, arising in the earliest dysplastic lesions. Here, we examined a mechanism of GUCY2C ligand transcriptional silencing by β-catenin/TCF signaling.
methodsWe performed RNA sequencing analysis of 4 unique conditional human colon cancer cell models of β-catenin/TCF signaling to map the core Wnt-transcriptional program. We then performed a comparative analysis of orthogonal approaches, including luciferase reporters, chromatin immunoprecipitation sequencing, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) knockout, and CRISPR epigenome editing, which were cross-validated with human tissue chromatin immunoprecipitation sequencing datasets, to identify functional gene enhancers mediating GUCY2C ligand loss.
resultsRNA sequencing analyses reveal the GUCY2C hormones as 2 of the most sensitive targets of β-catenin/TCF signaling, reflecting transcriptional repression. The GUCY2C hormones share an insulated genomic locus containing a novel locus control region upstream of the guanylin promoter that mediates the coordinated silencing of both genes. Targeting this region with CRISPR epigenome editing reconstituted GUCY2C ligand expression, overcoming gene inactivation by mutant β-catenin/TCF signaling.
conclusionsThese studies reveal DNA elements regulating corepression of GUCY2C ligand transcription by β-catenin/TCF signaling, reflecting a novel pathophysiological step in tumorigenesis. They offer unique genomic strategies that could reestablish hormone expression in the context of canonical oncogenic mutations to reconstitute the GUCY2C axis and oppose transformation.
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