Abstract 1444: Wnt/β-catenin/TCF signaling suppresses GUCY2C hormone transcription by silencing p38

Sporadic colorectal cancers (CRCs) are initiated by APC mutations inducing aberrant β-catenin/TCF signaling regulating gene transcription. Similarly, the guanylyl cyclase C (GUCY2C) tumor suppressive axis is universally silenced in CRC. While the GUCY2C receptor is retained, transcriptional silencing of its paracrine hormones guanylin and uroguanylin by β-catenin/TCF signaling is among the earliest events in colorectal transformation. Moreover, suppression of the β-catenin/TCF pathway reconstitutes hormone expression. P38 is a tumor suppressor, and its loss promotes tumorigenesis in chemical and genetic mouse models of CRC. We aim to identify mechanisms by which β-catenin/TCF signaling silences the transcription of GUCY2C hormones to enable targeted reconstitution of ligand expression to prevent CRC. Here, we employed four human CRC cell lines with conditional β-catenin/TCF signaling and healthy human and mouse intestinal organoid models to explore the role of p38 in oncogenic transcriptional signaling. Indeed, toggling oncogenic β-catenin/TCF activity regulates p38 phosphorylation and downstream signaling, suggesting that β-catenin/TCF gain-of-function represses the p38 pathway. Further, pharmacological and genetic repression of p38 activity recapitulates β-catenin/TCF gain-of-function and directly eliminates GUCY2C hormone expression. Finally, beyond GUCY2C hormones, regulation of ∼80% of a core set of β-catenin/TCF-dependent genes common to human CRC cells is controlled by p38 signaling. Here, we reveal β-catenin/TCF regulation of p38 activity and its role in mediating transcriptional regulation of gene expression underlying nuclear oncogenic signaling in CRC. Citation Format: Ariana A. Entezari, Adi Caspi, Jasmine R. Alvarez, Jeffrey A. Rappaport, Adam E. Snook, Scott A. Waldman. Wnt/β-catenin/TCF signaling suppresses GUCY2C hormone transcription by silencing p38 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1444.