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<p>Alternative RNA splicing is a fundamental mechanism for enhancing proteomic diversity, and its dysregulation is a hallmark of cancer progression. However, the dynamic regulatory networks controlling oncogenic splicing events remain poorly understood. Our previous work identified the inclusion of <i>CLSTN1</i> exon 11 as critical for the epithelial-to-mesenchymal transition (EMT). Here, we demonstrate that this splicing event promotes breast cancer metastasis by enhancing cell migration, invasion, and the generation of circulating tumor cells (CTCs) in vivo. To translate this finding into a therapeutic strategy, we developed splice-switching antisense oligonucleotides (ASOs) that effectively reverse exon 11 inclusion and suppress cancer cell migration. Furthermore, through systematic screening, we identified the RNA-binding protein TIA1 as a key suppressor of exon 11 inclusion. TIA1 inhibits EMT and metastasis, but its function is antagonized during EMT by phosphorylation mediated by the kinase DAPK3, which is upregulated in this process. This work defines a novel DAPK3-TIA1-CLSTN1 splicing axis that drives breast cancer metastasis, revealing new layers of post-transcriptional regulation and presenting promising therapeutic avenues for targeting pro-metastatic splicing.</p><p></p>

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TIA1 depletion enhances CLSTN1 exon 11 inclusion to facilitate Epithelial-to-Mesenchymal transition and breast cancer metastasis

  • 期刊论文

  • 发表日期：

    2026年6月1日

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  • Yaxuan Sun,
  • Rongrong Feng,
  • Xun Zhou,
  • Wuqin Xu,
  • Huimin Du,
  • Xiezong Hu,
  • Liang Chen,
  • Yongping Cai,
  • Xiaohui Hu

摘要

Alternative RNA splicing is a fundamental mechanism for enhancing proteomic diversity, and its dysregulation is a hallmark of cancer progression. However, the dynamic regulatory networks controlling oncogenic splicing events remain poorly understood. Our previous work identified the inclusion of CLSTN1 exon 11 as critical for the epithelial-to-mesenchymal transition (EMT). Here, we demonstrate that this splicing event promotes breast cancer metastasis by enhancing cell migration, invasion, and the generation of circulating tumor cells (CTCs) in vivo. To translate this finding into a therapeutic strategy, we developed splice-switching antisense oligonucleotides (ASOs) that effectively reverse exon 11 inclusion and suppress cancer cell migration. Furthermore, through systematic screening, we identified the RNA-binding protein TIA1 as a key suppressor of exon 11 inclusion. TIA1 inhibits EMT and metastasis, but its function is antagonized during EMT by phosphorylation mediated by the kinase DAPK3, which is upregulated in this process. This work defines a novel DAPK3-TIA1-CLSTN1 splicing axis that drives breast cancer metastasis, revealing new layers of post-transcriptional regulation and presenting promising therapeutic avenues for targeting pro-metastatic splicing.