p38α MAPK integrates opposing oncogenic APC/β-catenin/TCF and GUCY2C tumor-suppressor axes in colorectal cancer
- 1Thomas Jefferson University
Abstract
Introduction: Sporadic colorectal cancers (CRCs) form following initiating APC mutations, inducing constitutive {beta}-catenin/TCF signaling. Similarly, the guanylyl cyclase C (GUCY2C) tumor suppressor axis is universally silenced in CRC. While the GUCY2C receptor is retained, loss of its paracrine hormones guanylin (GUCA2A) and uroguanylin (GUCA2B) is among the earliest events in transformation. Mutant APC/{beta}-catenin/TCF signaling driving CRC transcriptionally silences GUCY2C hormone expression while suppressing that oncogenic pathway reconstitutes hormone production opposing tumorigenesis. p38 opposes tumor initiation, and its loss promotes transformation in chemical and genetic mouse models of CRC. In healthy intestine, p38 supports a gradient of epithelial differentiation along the crypt-surface axis. Here, we reveal that p38 links regulation of oncogenic APC/{beta}-catenin/TCF signaling and GUCY2C hormone expression. Methods: Regulation of p38 by APC/{beta}-catenin/TCF signaling was defined in four genetically engineered human CRC cell lines with conditional oncogenic APC/{beta}-catenin/TCF signaling and healthy human colon organoids. Expression of p38 was eliminated from conditional human CRC cell lines by pharmacological inhibition, RNA knockdown, and CRISPR/Cas9 gene editing. Transcriptomic analysis of these cells by RNA sequencing defined the set of genes regulated by APC/{beta}-catenin/TCF signaling controlled through p38. Results: In CRC cell lines, APC/{beta}-catenin/TCF signaling suppressed p38 phosphorylation and activity, whereas inhibition of APC/{beta}-catenin/TCF restored p38 signaling. In the absence of APC/{beta}-catenin/TCF signaling, inhibiting p38 repressed GUCY2C hormone expression. Inhibiting APC/{beta}-catenin/TCF signaling enriched phosphorylated p38 at the GUCA2A promoter. In that context, analysis of the CPTAC proteomic database revealed that phosphorylation of p38 and its upstream kinases MKK3 and MKK4 was reduced in human CRC. Finally, transcriptomic analysis revealed that p38 is a critical signaling node controlling the expression of a substantial subset of APC/{beta}-catenin/TCF-regulated genes in human CRC cells and patient tumors. Conclusions: APC/{beta}-catenin/TCF signaling inhibits p38 phosphorylation and transcriptional activity, suppressing GUCA2A and GUCA2B expression and functionally silencing the retained GUCY2C receptor. These findings identify p38 as a signaling intermediary integrating oncogenic APC/{beta}-catenin/TCF activity to extinction of the GUCY2C tumor-suppressor axis and reveal a broader p38-dependent component of the APC/{beta}-catenin/TCF-regulated transcriptome.
Related
- Computational screening of oncogenic genetic variations in tumor suppressor proteins driving gastric cancer pathogenesis
- FBXO17 regulates the malignant progression of colorectal cancer via the Wnt/β-catenin pathway
- CAST as a Tumor-Specific Suppressor in Colorectal Cancer: Discovery Through Integrative Analysis of Unannotated Isoforms, Proteomics, and Epigenetic Regulation
- Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer
- Fibrinogen Alpha Chain (FGA) Associates With Epithelial-Mesenchymal Transition, Stemness, and the USP-Catenin Complex in Colorectal Cancer.
BibTeX
@misc{entezari2026p38α,
title = {{p38α MAPK integrates opposing oncogenic APC/β-catenin/TCF and GUCY2C tumor-suppressor axes in colorectal cancer}},
author = {A. A. Entezari and A. Caspi and J. R. Alvarez and A. E. Evans and J. A. Rappaport and T. J. M. Kuret and A. S. Doermann and R. Mitra and A. E. Snook and S. A. Waldman},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756833},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756833v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - p38α MAPK integrates opposing oncogenic APC/β-catenin/TCF and GUCY2C tumor-suppressor axes in colorectal cancer
AU - A. A. Entezari
AU - A. Caspi
AU - J. R. Alvarez
AU - A. E. Evans
AU - J. A. Rappaport
AU - T. J. M. Kuret
AU - A. S. Doermann
AU - R. Mitra
AU - A. E. Snook
AU - S. A. Waldman
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756833
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756833v1
AB - Introduction: Sporadic colorectal cancers (CRCs) form following initiating APC mutations, inducing constitutive {beta}-catenin/TCF signaling. Similarly, the guanylyl cyclase C (GUCY2C) tumor suppressor axis is universally silenced in CRC. While the GUCY2C receptor is retained, loss of its paracrine hormones guanylin (GUCA2A) and uroguanylin (GUCA2B) is among the earliest events in transformation. Mutant APC/{beta}-catenin/TCF signaling driving CRC transcriptionally silences GUCY2C hormone expression while suppressing that oncogenic pathway reconstitutes hormone production opposing tumorigenesis. p38 opposes tumor initiation, and its loss promotes transformation in chemical and genetic mouse models of CRC. In healthy intestine, p38 supports a gradient of epithelial differentiation along the crypt-surface axis. Here, we reveal that p38 links regulation of oncogenic APC/{beta}-catenin/TCF signaling and GUCY2C hormone expression. Methods: Regulation of p38 by APC/{beta}-catenin/TCF signaling was defined in four genetically engineered human CRC cell lines with conditional oncogenic APC/{beta}-catenin/TCF signaling and healthy human colon organoids. Expression of p38 was eliminated from conditional human CRC cell lines by pharmacological inhibition, RNA knockdown, and CRISPR/Cas9 gene editing. Transcriptomic analysis of these cells by RNA sequencing defined the set of genes regulated by APC/{beta}-catenin/TCF signaling controlled through p38. Results: In CRC cell lines, APC/{beta}-catenin/TCF signaling suppressed p38 phosphorylation and activity, whereas inhibition of APC/{beta}-catenin/TCF restored p38 signaling. In the absence of APC/{beta}-catenin/TCF signaling, inhibiting p38 repressed GUCY2C hormone expression. Inhibiting APC/{beta}-catenin/TCF signaling enriched phosphorylated p38 at the GUCA2A promoter. In that context, analysis of the CPTAC proteomic database revealed that phosphorylation of p38 and its upstream kinases MKK3 and MKK4 was reduced in human CRC. Finally, transcriptomic analysis revealed that p38 is a critical signaling node controlling the expression of a substantial subset of APC/{beta}-catenin/TCF-regulated genes in human CRC cells and patient tumors. Conclusions: APC/{beta}-catenin/TCF signaling inhibits p38 phosphorylation and transcriptional activity, suppressing GUCA2A and GUCA2B expression and functionally silencing the retained GUCY2C receptor. These findings identify p38 as a signaling intermediary integrating oncogenic APC/{beta}-catenin/TCF activity to extinction of the GUCY2C tumor-suppressor axis and reveal a broader p38-dependent component of the APC/{beta}-catenin/TCF-regulated transcriptome.
ER -