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Functional significance of U2AF1 S34F mutations in lung adenocarcinomas
Mohammad S Esfahani1,2,3, Luke J Lee1, Young-Jun Jeon1,3
1Stanford Cancer Institute, Stanford University, Stanford, USA.
Abstract:
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.
Insights
Mutations in U2AF1 (U2 auxiliary factor 1) co-occur with ROS1 translocations in lung adenocarcinoma. This interaction affects RNA splicing, promotes epithelial-mesenchymal transition, and increases tumor cell invasion.
Area of Science:
- Molecular Biology
- Cancer Genetics
- RNA Splicing
Background:
- The role of U2AF1 mutations in lung adenocarcinoma (LUAD) is not fully understood.
- U2AF1 mutations are increasingly recognized in various cancers.
Purpose of the Study:
- To investigate the functional consequences of U2AF1 S34F mutations in LUAD.
- To characterize the interplay between U2AF1 S34F and ROS1 translocations.
Main Methods:
- Transcriptome-wide profiling of RNA binding and alternative splicing.
- Analysis of U2AF1 S34F binding preferences and splicing modulation.
- Assessment of gene expression changes related to epithelial-mesenchymal transition (EMT) and cell invasion.
Main Results:
- U2AF1 S34F preferentially binds and alters splicing of introns with CAG trinucleotides at 3' splice junctions.
- S34F mutation induced alternative splicing of skipped exons and altered 3' splice site cross-linking.
- U2AF1 S34F expression promoted EMT, increased tumor cell invasion, and favored a specific SLC34A2-ROS1 isoform.
Conclusions:
- A mechanistic link exists between U2AF1 S34F mutations and ROS1 translocations in LUAD.
- This interaction contributes to tumor progression through altered splicing and EMT induction.
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