APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis

ABSTRACT

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

KEYWORDS:

• GUCA2A
• guanylyl cyclase C
• colorectal cancer
• transcriptional regulation
• chemoprevention

Acknowledgments

S.A.W. is the Samuel MV Hamilton Professor at Thomas Jefferson University. Results are, in part, based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/

Disclosure of Potential Conflicts of Interest

SAW is a member of the Board and Chair of the Scientific Advisory Board of, and AES is a consultant for, Targeted Diagnostics & Therapeutics, Inc. which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work.

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Additional information

Funding

Supported by grants to SAW from NIH (1R01 CA204881, 1R01 CA206026, P30 CA56036), Department of Defense Congressionally Directed Medical Research Program W81XWH-17-PRCRP-TTSA, The Courtney Ann Diacont Memorial Foundation, and Targeted Diagnostic & Therapeutics, Inc. and to AES (Department of Defense Congressionally Directed Medical Research Program W81XWH-17-1-0299, PhRMA Foundation, the W.W. Smith Charitable Trust, and Margaret Q. Landenberger Research Foundation). E.S.B., J.A.R., and A.M.P. were supported by Ruth Kirschstein Individual Fellowship Awards (F30 CA180500, F30 CA232469, and F31 CA225123, respectively). J.A.R was supported by a pre-doctoral fellowship from the PhRMA Foundation. B.B. and E.C. were supported by NIH institutional award T32 GM008562 for Postdoctoral Training in Clinical Pharmacology.