Functional significance of U2AF1 S34F mutations in lung adenocarcinomas.,Nature Communications

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Functional significance of U2AF1 S34F mutations in lung adenocarcinomas.
Nature Communications ( IF 14.7 ) Pub Date : 2019-12-13 , DOI: 10.1038/s41467-019-13392-y
Mohammad S Esfahani _{1,

2,

3} , Luke J Lee ₁ , Young-Jun Jeon _{1,

3} , Ryan A Flynn ₄ , Henning Stehr _{1,

5} , Angela B Hui _{1,

3} , Noriko Ishisoko ₆ , Eric Kildebeck ₇ , Aaron M Newman _{8,

9} , Scott V Bratman _{3,

8,

10} , Matthew H Porteus ₇ , Howard Y Chang _{11,

12} , Ash A Alizadeh _{1,

2,

12} , Maximilian Diehn _{1,

3,

8}

Affiliation

Stanford Cancer Institute, Stanford University, Stanford, USA.
Division of Oncology, Department of Medicine, Stanford University, Stanford, USA.
Department of Radiation Oncology, Stanford University, Stanford, USA.
Department of Chemistry, Stanford University, Stanford, USA.
Department of Pathology, Stanford University, Stanford, CA, USA.
Department of Bioengineering, Stanford University, Stanford, USA.
Department of Pediatrics, Stanford University, Stanford, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, USA.
Department of Biomedical Data Science, Stanford University, Stanford, USA.
Department of Radiation Oncology, University of Toronto, Toronto, CA, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
Division of Hematology, Department of Medicine, Stanford University, Stanford, USA.

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.

中文翻译：

U2AF1 S34F 突变在肺腺癌中的功能意义。

U2AF1 突变在肺腺癌 (LUAD) 中的功能作用仍不完全清楚。在这里，我们报告了 LUAD 中 U2AF1 S34F 突变与 ROS1 易位的显着共现。为了表征这种相互作用，我们分析了 S34F 对包含 ROS1 易位的细胞中 RNA 结合和选择性剪接的转录组范围分布的影响。与其野生型对应物相比，U2AF1 S34F 优先结合并调节 3' 剪接点处含有 CAG 三核苷酸的内含子的剪接。 S34F 的存在引起 3' 剪接位点交联的变化，这与跳跃外显子的选择性剪接显着相关。 U2AF1 S34F 诱导参与上皮间质转化 (EMT) 的基因表达并增加肿瘤细胞侵袭。最后，S34F 增加了长 SLC34A2-ROS1 亚型相对于短 SLC34A2-ROS1 亚型的剪接，这也与增强的侵袭性相关。综上所述，我们的结果表明 LUAD 中突变型 U2AF1 和 ROS1 之间存在机械相互作用。

更新日期：2019-12-13

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