A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements

Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer.

Automated summary

The abnormal alternative splicing influenced by RNA structural coding plays a role in breast cancer metastasis. A novel structural splicing enhancer was identified to interact with SNRPA1 protein, promoting cassette exon inclusion and enhancing metastatic abilities. This study reveals a noncanonical regulatory role of SNRPA1 as a prometastatic splicing enhancer in breast cancer.