Functional significance of U2AF1 S34F mutations in lung adenocarcinomas.
Mohammad S EsfahaniLuke J LeeYoung-Jun JeonRyan A FlynnHenning StehrAngela B HuiNoriko IshisokoEric KildebeckAaron M NewmanScott V BratmanMatthew H PorteusHoward Y ChangAsh A AlizadehMaximillian DiehnPublished in: Nature communications (2019)
The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3' splice junctions. The presence of S34F caused a shift in cross-linking at 3' splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.
Keyphrases
- atrial fibrillation
- epithelial mesenchymal transition
- cell death
- wild type
- dna damage
- reactive oxygen species
- cell cycle arrest
- induced apoptosis
- gene expression
- poor prognosis
- signaling pathway
- transforming growth factor
- rna seq
- genome wide
- high glucose
- dna methylation
- long non coding rna
- transcription factor
- stress induced