Antisense oligonucleotide-mediated TRA2β poison exon inclusion induces the expression of a lncRNA with anti-tumor effects

Nathan K. Leclair, Mattia Brugiolo, SungHee Park, Maeva Devoucoux, Laura Urbanski, Brittany L. Angarola, Marina Yurieva and Olga Anczuków ()
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Nathan K. Leclair: The Jackson Laboratory for Genomic Medicine
Mattia Brugiolo: The Jackson Laboratory for Genomic Medicine
SungHee Park: The Jackson Laboratory for Genomic Medicine
Maeva Devoucoux: The Jackson Laboratory for Genomic Medicine
Laura Urbanski: The Jackson Laboratory for Genomic Medicine
Brittany L. Angarola: The Jackson Laboratory for Genomic Medicine
Marina Yurieva: The Jackson Laboratory for Genomic Medicine
Olga Anczuków: The Jackson Laboratory for Genomic Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Upregulated expression of the oncogenic splicing factor TRA2β occurs in human tumors partly through decreased inclusion of its autoregulatory non-coding poison exon (PE). Here, we reveal that low TRA2β-PE inclusion negatively impacts patient survival across several tumor types. We demonstrate the ability of splice-switching antisense oligonucleotides (ASOs) to promote TRA2β-PE inclusion and lower TRA2β protein levels in pre-clinical cancer models. TRA2β-PE-targeting ASOs induce anti-cancer phenotypes and widespread transcriptomic alterations with functional impact on RNA processing, mTOR, and p53 signaling pathways. Surprisingly, the effect of TRA2β-PE-targeting ASOs on cell viability are not phenocopied by TRA2β knockdown. Mechanistically, we find that the ASO functions by both decreasing TRA2β protein and inducing the expression of TRA2β-PE-containing transcripts that act as long non-coding RNAs to sequester nuclear proteins. Finally, TRA2β-PE-targeting ASOs are toxic to preclinical 3D organoid and in vivo patient-derived xenograft models. Together, we demonstrate that TRA2β-PE acts both as a regulator of protein expression and a long-noncoding RNA to control cancer cell growth. Drugging oncogenic splicing factors using PE-targeting ASOs is a promising therapeutic strategy.

Date: 2025
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DOI: 10.1038/s41467-025-56913-8

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