APC-β-Catenin-TCF Signaling Silences the GUCY2C Tumor Suppressor Axis in Colorectal Cancer
Colorectal cancer is the second leading cause of cancer mortality in the United States, representing an unmet need for prevention strategies. 80% of sporadic colorectal cancers arise from mutations of adenomatous polyposis coli (APC) or its downstream target, β-catenin. These mutations lead to stabilization and nuclear accumulation of β-catenin, driving a transcriptional program underlying tumorigenesis. While aberrant APC/β-catenin signaling is a well-established driver of colorectal cancer, downstream mechanisms regulating transformation remain incompletely understood. In this context, a novel tumor suppressor, guanylyl cyclase C (GUCY2C), offers an opportunity to advance the prevention and treatment of the disease. GUCY2C is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Together with its endogenous ligands, guanylin (GUCA2A) and uroguanylin (GUCA2B), it regulates intestinal fluid secretion, tissue architecture, and canonical cancer signaling networks. GUCY2C agonists reduce epithelial transformation in genetic, carcinogen, and inflammatory mouse models of intestinal tumorigenesis. Intriguingly, the GUCY2C ligands are among the most commonly lost gene products in colorectal cancer. Their loss occurs early in transformation and arises in lesions harboring APC mutations. Together, these observations suggest a pathophysiological model in which transformation reduces GUCY2C ligand expression, silencing GUCY2C signaling and driving tumorigenesis. Here, we examine a mechanistic basis for GUCY2C ligand loss in colorectal cancer and test the hypothesis that ligand loss is an early and universal step in tumorigenesis, arising directly from the tumor-initiating mutations in APC and the subsequent reprogramming of nuclear transcription by β-catenin/TCF. Our results demonstrate that ligand loss is an evolutionarily conserved, and importantly, reversible event. Ligand loss arises from transcriptional silencing by the APC-β-catenin-TCF axis, mediated by a novel locus control region upstream of GUCA2A. This DNA element coordinates the silencing of both GUCY2C ligands (GUCA2A and GUCA2B) within an insulated transcriptional locus and can be targeted with CRISPR-Cas9 epigenome editing to reconstitute expression even in the context of mutant β-catenin/TCF signaling. These insights inform an evolving therapeutic hypothesis that describes colorectal cancer as a reversible disease of hormone insufficiency, rather than an irreversible disease of genetic mutation, which could be overcome through oral GUCY2C agonists or endogenous ligand reconstitution.
Rappaport, Jeffrey, "APC-β-Catenin-TCF Signaling Silences the GUCY2C Tumor Suppressor Axis in Colorectal Cancer" (2023). ETD Collection for Thomas Jefferson University. AAI28412664.