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AKAP8 inhibits tumor metastasis by antagonizing EMT-associated RNA alternative splicing

ABSTRACT: Tumor metastasis is the most lethal attribute of breast cancer, and the epithelial-mesenchymal transition (EMT) plays an important role in this process. Alternative splicing has been shown to causally contribute to EMT; however, the scope of critical splicing events and the regulatory network of splicing factors that govern them remain largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as an EMT 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 binds to RNA directly and alters splicing outcomes. Genome-wide analysis revealed that AKAP8-mediated splicing events, specifically in epithelial cells, are reversely regulated during EMT, suggesting that AKAP8 maintains an epithelial cell-state splicing program. Experimental manipulation of a newly identified AKAP8 splicing target calsyntenin-1 (CLSTN1) revealed that splice isoform switching of CLSTN1 is crucial for EMT. Mining breast cancer patient data supports the experimental findings and AKAP8 expression and the alternative splicing of CLSTN1 predict patient survival. Our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139074 | GEO | 2019/12/11

REPOSITORIES: GEO

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Cell-type restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

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2014-06-03 | E-GEOD-57243 | biostudies-arrayexpress

Cell-type restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing

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Project description:The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome-scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they co-regulate a set of cassette exon events, with the majority showing discordant splicing regulation. hnRNPM discordantly regulated splicing events show a positive correlation with splicing during EMT while concordant splicing events do not, highlighting the antagonistic role of hnRNPM and ESRP1 during EMT. Motif enrichment analysis near co-regulated exons identifies guanine-uridine rich motifs downstream of hnRNPM-repressed and ESRP1-enhanced exons, supporting a model of competitive binding to these cis-elements to antagonize alternative splicing. The set of co-regulated exons are enriched in genes associated with cell-migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of co-regulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtypes. In conclusion, hnRNPM and ESRP1 co-regulate antagonistically a set of alternative splicing events that occur during EMT. This regulation is likely mediated through competition for the same intronic binding sites downstream of variable exons. hnRNPM and ESRP1 regulated splicing events are associated with breast cancer survival.

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RNA-sequencing in immortalized human mammary epithelial cells

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