Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress.
Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress.
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DOI：
10.14348/molcells.2018.0176
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发表时间：
2018-08-31
影响因子：
3.8
通讯作者：
Kim J
中科院分区：
文献类型：
--
作者：
Kim S;Park C;Jun Y;Lee S;Jung Y;Kim J
剪接体成分的突变与各种类型癌症的致癌作用有关。最常见的突变之一是 U2AF1 S34F 错义突变。尽管这种突变也常见于其他癌症类型，包括肺腺癌（LUAD），但对该突变的功能分析在很大程度上仅限于血液恶性肿瘤。我们研究了野生型 (wt) U2AF1 的敲除 (KD) 和两种剪接变体 S34F 突变蛋白的异位表达对 A549 肺癌细胞中选择性剪接 (AS) 模式和细胞周期进展的影响。我们证明了不同 AS 事件的诱导和不同亚阶段有丝分裂的破坏是由突变蛋白的 KD 和异位表达引起的。重要的是，与 U2AF1 S34F 突变的 LUAD 患者中观察到的剪接模式相比，S34F 突变体而非 KD 的异位表达被证明会导致参与细胞周期进展的几个基因中常见的 AS 事件。因此，我们的研究指出 U2AF1 S34F 突变蛋白在诱导细胞周期失调和有丝分裂应激中发挥积极作用。此外，我们在此描述的选择性剪接基因可能代表肺癌发展的新的潜在标志物。
Mutations in spliceosome components have been implicated in carcinogenesis of various types of cancer. One of the most frequently found is U2AF1 S34F missense mutation. Functional analyses of this mutation have been largely limited to hematological malignancies although the mutation is also frequently seen in other cancer types including lung adenocarcinoma (LUAD). We examined the impact of knockdown (KD) of wild type (wt) U2AF1 and ectopic expression of two splice variant S34F mutant proteins in terms of alternative splicing (AS) pattern and cell cycle progression in A549 lung cancer cells. We demonstrate that induction of distinct AS events and disruption of mitosis at distinct sub-stages result from KD and ectopic expression of the mutant proteins. Importantly, when compared with the splicing pattern seen in LUAD patients with U2AF1 S34F mutation, ectopic expression of S34F mutants but not KD was shown to result in common AS events in several genes involved in cell cycle progression. Our study thus points to an active role of U2AF1 S34F mutant protein in inducing cell cycle dysregulation and mitotic stress. In addition, alternatively spliced genes which we describe here may represent novel potential markers of lung cancer development.