Antisense oligonucleotide-mediated TRA2β poison exon inclusion induces the expression of a lncRNA with anti-tumor effects
Nathan K. Leclair, Mattia Brugiolo, SungHee Park, Maëva Devoucoux, Laura M. Urbanski, Brittany Angarola, Marina Yurieva, Olga Anczuków
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. The oncogenic splicing factor TRA2β is reported to be upregulated in human cancers partly by increased TRA2β poison exon (PE) skipping. Here the authors show that forced inclusion of this PE using antisense oligonucleotides depletes TRA2β protein levels and generates long non-coding RNAs that sequester nuclear proteins, leading to cancer toxicity.