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Post-transcriptional control of SRSF9 promotes the epithelial-to-mesenchymal transition (EMT) in colorectal cancer cells

Rao, C.; Svoboda, R. A.; Southekal, S.; Vieira, H. M.; Huisman, D. H.; Chatterjee, D.; Guda, C.; Fisher, K. W.; Anczukow, O.; Lewis, R. E.

2022-05-17 cell biology
10.1101/2022.05.16.492181 bioRxiv
Show abstract

In human colorectal cancer (CRC) cells the Raf/MEK/ERK scaffold Kinase Suppressor of Ras 1 (KSR1)-dependent signaling is required for the epithelial-to-mesenchymal transition (EMT)-like phenotype. Here we show that KSR1 promotes the association of differentially spliced mRNA bearing recognition sites for the Serine/Arginine-Rich (SR) splicing factor SRSF9. CRISPR/Cas9 disruption of KSR1 destabilizes SRSF9 protein, which interacts preferentially with mRNA encoding Epithelial Stromal Interaction 1 (EPSTI1). EPSTI1 protein mediates Ras and KSR1-dependent induction of EMT. Analysis of EPSTI1 splice variants reveals that inclusion of exon 8 is critical to the ability of EPSTI1 to promote the E-to N-cadherin switch and CRC cell motile and invasive behavior. These data reveal a mechanism in CRC cells in which Ras-induced and KSR1-dependent signaling affects pre-mRNA splicing to control behaviors critical to cancer cell dissemination and metastasis.

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