TIA1缺失促进CLSTN1外显子11包含增强乳腺癌上皮间充质转化和转移

Abstract

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. The alternative text for this image may have been generated using AI.