# Functional characterization of CASP, a CUX1 isoform, reveals its tumor-promoting role in colorectal cancer via TRIM21-mediated signaling

## TL;DR

A specific variant of the CUX1 gene, called CASP, promotes colorectal cancer growth and spread by interacting with TRIM21 and activating cancer-related signaling pathways.

## Contribution

This study identifies CASP as a tumor-promoting isoform of CUX1 and reveals its mechanism of action via TRIM21-mediated signaling in colorectal cancer.

## Key findings

- CASP is upregulated in colorectal adenomas and carcinomas and promotes tumor growth and metastasis.
- CASP interacts with TRIM21, leading to its degradation and activation of the MAPK signaling pathway.
- High CASP expression correlates with poor prognosis and specific genetic profiles in CRC patients.

## Abstract

CUT-like homeobox 1 (CUX1) is a transcription factor with dual roles in tumorigenesis. Among its splice variants, the Golgi-localized cut alternative spliced product (CASP) lacks DNA-binding domains, and its functional significance has remained largely unexplored. In this study, we identify CASP as a potential oncoprotein that is specifically upregulated in colorectal adenomas and carcinomas. Genetic silencing of CASP suppressed the proliferation and migration of colorectal cancer (CRC) cells, while its overexpression enhanced tumor growth and metastatic potential both in vitro and in vivo. Mechanistically, CASP interacts with the E3 ubiquitin ligase TRIM21 and promotes its ubiquitination and proteasomal degradation, leading to subsequent activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Clinically, CASP expression was correlated with mismatch repair (MMR)/microsatellite instability (MSI) status and TP53 mutational profiles. These findings implicate CASP in CRC progression and support its potential as a prognostic biomarker and therapeutic target by disrupting CASP-driven signaling.

•CASP (CUX1 splice isoform) is dysregulated in colorectal cancer (CRC)•CASP correlates with MMR/MSI status and TP53 mutation status in CRC•High CASP expression is associated with poor prognosis in CRC•CASP binds TRIM21, promotes proteasomal degradation, and activates MAPK in CRC

CASP (CUX1 splice isoform) is dysregulated in colorectal cancer (CRC)

CASP correlates with MMR/MSI status and TP53 mutation status in CRC

High CASP expression is associated with poor prognosis in CRC

CASP binds TRIM21, promotes proteasomal degradation, and activates MAPK in CRC

Biological sciences; Molecular biology; Cell biology