Aberrant 3'UTR splicing drives FUS-dependent mRNA condensates and prevents β-catenin from adherens junctions to promote cancer aggressiveness
Abstract
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 {beta}-catenin mRNA direct distinct subcellular localization of {beta}-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 {beta}-catenin function is exquisitely dependent on its subcellular distribution between adherens junctions and the nucleus, this aberrant 3'UTR isoform reprograms {beta}-catenin localization. By sequestering {beta}-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.
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- biorxiv v1 2026-07-09 source ↗
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bioRxiv Cell Biology @biorxiv-cellbio.bsky.social · 6030 followers neutral
Aberrant 3'UTR splicing drives FUS-dependent mRNA condensates and prevents β-catenin from adherens junctions to promote cancer aggressiveness https://www.biorxiv.org/content/10.64898/2026.07.01.735936v1
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bioRxivpreprint @biorxivpreprint.bsky.social · 8895 followers neutral
Aberrant 3'UTR splicing drives FUS-dependent mRNA condensates and prevents β-catenin from adherens junctions to promote cancer aggressiveness https://www.biorxiv.org/content/10.64898/2026.07.01.735936v1