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 ARTICLE HISTORY

Silencing the intestinal GUCY2C tumor suppressor axis requires APC loss of heterozygosity

“…Loss of GUCY2C hormone expression is an early event along the continuum of colorectal cancer that aligns with mutations in the APC-β-catenin signaling pathway. 2,31,34 Previously, we demonstrated that biallelic loss of APC increases Wnt signaling which, in turn, represses GUCY2C hormone expression, supporting a role for this process in tumor progression. 34 Here, we explored the effect of monoallelic APC loss (APC heterozygosity) on hormone expression as a potential mechanism contributing to genetic vulnerability, by silencing the GUCY2C axis, that could promote APC LOH and tumor initiation.…”

“…34 These studies demonstrated that oncogenic APC-β-catenin signaling silences guanylin mRNA and loss of guanylin expression was dependent on a canonical TCF-dependent mechanism. 34 These observations underscore the established pathophysiological association of hormone loss with colorectal tumorigenesis across species. 29,[31][32][33][34] They suggest a role for hormone repression silencing GUCY2C in mechanisms contributing to tumor progression, for example through hyperproliferation, desmoplasia, chromosomal instability, and DNA hyper-mutation, [17][18][19][20][21]33 reflecting dependence of this repression on LOH and APC biallelic loss.…”

“…[16][17][18][19][20][21]44,45 In that context, loss of guanylin and uroguanylin, which silences GUCY2C signaling, occurs at the earliest stage of intestinal transformation by a mechanism that is conserved across species. 31,32,34 Previously, we demonstrated that GUCY2C hormone expression is eliminated by a dysregulated nuclear β-catenin-dependent transcriptional mechanism reflecting APC LOH in mice and humans. 34 Indeed, we have identified a pathophysiological model in which guanylin hormone expression is eliminated as a direct downstream consequence of mutant APC-β-catenin-TCF nuclear transcriptional reprogramming.…”

“…34 Indeed, we have identified a pathophysiological model in which guanylin hormone expression is eliminated as a direct downstream consequence of mutant APC-β-catenin-TCF nuclear transcriptional reprogramming. 34 These studies demonstrated that oncogenic APC-β-catenin signaling silences guanylin mRNA and loss of guanylin expression was dependent on a canonical TCF-dependent mechanism. 34 These observations underscore the established pathophysiological association of hormone loss with colorectal tumorigenesis across species.…”

“…29,31,32 Moreover, loss of these paracrine hormones occurs universally at the earliest stages of tumorigenesis in mice and humans coincident with APC LOH. 29,[31][32][33][34] In contrast, GUCY2C expression appears to be preserved in most primary and metastatic colorectal tumors. [33][34][35][36][37] In the context of these observations, we explored the hypothesis that paracrine hormone loss, which in turn silences GUCY2C, is an obligatory step contributing to the genetic vulnerability underlying LOH which establishes the premalignant field.…”