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.

异常的选择性剪接是癌症的一个标志，但控制这一过程的潜在监管程序仍然很大程度上未知。在这里，我们报告了一项系统性的工作，以破译在乳腺癌转移过程中形成病理剪接的RNA结构密码。我们发现了一种以前未知的结构剪接增强子，它在盒式外显子附近富集，并在高度转移的细胞中增加了内含物。我们发现剪接体蛋白小核核糖核蛋白多肽 A' (SNRPA1) 与这些增强子相互作用以促进盒式外显子包含。这种相互作用增强了转移性肺定植和癌细胞侵袭，部分是通过 SNRPA1 介导的PLEC选择性剪接调节，而这可以通过剪接调节吗啉代来抵消。我们的研究结果确立了 SNRPA1 作为乳腺癌前转移剪接增强子的非典型调节作用。