Aberrant 3′UTR splicing drives FUS-dependent mRNA condensates and prevents β-catenin from adherens junctions to promote cancer aggressiveness

The protein-coding sequence has long been considered the primary determinant of protein function. Alternative splicing within 3′UTRs (AS-3′UTRs) generates multiple transcript isoforms from a single gene, yet their roles in protein function and disease relevance remain largely unexplored. Through systematic transcriptome-wide identification of cancer-associated AS-3′UTRs, we uncover that AS-3′UTRs of β-catenin mRNA direct distinct subcellular localization of β-catenin mRNA isoforms. Specifically, an aberrantly spliced 3′UTR isoform promotes cytoplasmic mRNA condensate formation through FUS binding to a cancer-associated alternative exon (Exon 16A). Because β-catenin function is exquisitely dependent on its subcellular distribution between adherens junctions and the nucleus, this aberrant 3′UTR isoform reprograms β-catenin localization. By sequestering β-catenin in the cytoplasm, the aberrant 3′UTR isoform prevents its incorporation into E-cadherin-based adherens junctions, thereby inducing epithelial–mesenchymal transition (EMT)-associated transcriptional programs. Notably, the expression signature of the aberrant 3′UTR isoform robustly correlates with poor clinical outcomes in colorectal cancer patients. Together, our findings reveal that AS-3′UTRs operate as a previously unrecognized post-transcriptional regulatory mechanism through which the untranslated region of mRNA, without altering a single amino acid, reprograms protein subcellular fate to drive oncogenic phenotypes.