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

Author

Listed:
  • Nathan K. Leclair

    (The Jackson Laboratory for Genomic Medicine
    UConn Health)

  • 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
    UConn Health)

  • 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
    UConn Health
    UConn Health)

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.

Suggested Citation

  • Nathan K. Leclair & Mattia Brugiolo & SungHee Park & Maeva Devoucoux & Laura Urbanski & Brittany L. Angarola & Marina Yurieva & Olga Anczuków, 2025. "Antisense oligonucleotide-mediated TRA2β poison exon inclusion induces the expression of a lncRNA with anti-tumor effects," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56913-8
    DOI: 10.1038/s41467-025-56913-8
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    References listed on IDEAS

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