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<p>Upregulated expression of the oncogenic splicing factor TRA2β occurs in&#xa0;human tumors partly through decreased inclusion of its autoregulatory non-coding poison exon <i>(PE</i>). Here, we reveal that low <i>TRA2β-PE</i> inclusion negatively impacts patient survival across several tumor types. We demonstrate the ability of splice-switching antisense oligonucleotides (ASOs) to promote <i>TRA2β-PE</i> inclusion and lower TRA2β protein levels in pre-clinical cancer models. <i>TRA2β-PE</i>-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 <i>TRA2β-PE</i>-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 <i>TRA2β-PE</i>-containing transcripts that act as long non-coding RNAs to sequester nuclear proteins. Finally, <i>TRA2β-PE</i>-targeting ASOs are toxic to preclinical 3D organoid and in vivo patient-derived xenograft models. Together, we demonstrate that <i>TRA2β-PE</i> acts both as a regulator of protein expression and a long-noncoding RNA to control cancer cell growth. Drugging oncogenic splicing factors using <i>PE</i>-targeting ASOs is a promising therapeutic strategy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月15日

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  • Nathan K. Leclair,
  • Mattia Brugiolo,
  • SungHee Park,
  • Maeva Devoucoux,
  • Laura Urbanski,
  • Brittany L. Angarola,
  • Marina Yurieva,
  • Olga Anczuków

摘要

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.