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

CUT-like homeobox 1 (<i>CUX1</i>) 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 <i>in vitro</i> and <i>in vivo</i>. 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 <i>TP53</i> 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.