Abstract
Alternative splicing has been shown to causally contribute to the epithelial–mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein–protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.
Highlights
Alternative splicing has been shown to causally contribute to the epithelial–mesenchymal transition (EMT) and tumor metastasis
Following our initial discovery that CD44 isoform switching is essential for EMT8, other studies have reported that epithelial cells that predominantly express CD44v demand an isoform switch to CD44s in order for cells to undergo EMT and for cancer cells to metastasize[17,18,19,20,21,22,23,24,25,26]
Given our observation that A kinase anchoring protein 8 (AKAP8) interacts with heterogeneous nuclear ribonucleoprotein M (hnRNPM) and regulates CD44 minigene splicing, we sought to interrogate whether AKAP8 regulates global alternative splicing, especially EMTrelated alternative splicing
Summary
Alternative splicing has been shown to causally contribute to the epithelial–mesenchymal transition (EMT) and tumor metastasis. The splicing activity of hnRNPM is partially restricted by an epithelial-specific splicing factor ESRP1 through competitive binding to the same RNA motifs, tightly controlling the switch of CD44 splice isoforms and transition of cell states during EMT9,10. In addition to this mode of direct competition through binding to RNA substrates, it is conceivable that hnRNPM-interacting splicing factors could influence hnRNPM’s activity and its function in promoting EMT. We demonstrate that both AKAP8 and its splicing target CLSTN1 accurately predict patient survival These results identify the splicing factor AKAP8 as a suppressor of EMT and metastatic cancer and shed lights on the mechanisms of EMT and tumor metastasis that are regulated at the level of alternative RNA splicing
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