Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA.
Nat Commun. 2021 Jul 30;12(1):4624. doi: 10.1038/s41467-021-24795-1.
AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.
AKT 磷酸化的 IWS1 通过在肺癌中活跃的途径调节选择性 RNA 剪接。在缺乏磷酸化 IWS1 的肺腺癌细胞中的 RNA-seq 研究，鉴定出 U2AF2 剪接变体的外显子 2 缺失。在这里，我们表明 U2AF2 mRNA 的外显子 2 包含是一个细胞周期依赖性过程，受 LEDGF/SRSF1 剪接复合物调节，其组装受 IWS1 磷酸化依赖性沉积的靶基因的组蛋白 H3K36me3 标记控制。外显子 2 缺失的 U2AF2 mRNA 编码一个丝氨酸-精氨酸-富含（RS）结构域缺失的 U2AF65，其在 CDCA5 前体 mRNA 加工中存在缺陷。这导致编码 Sororin 的 CDCA5 蛋白下调，Sororin 是 ERK 的磷酸化靶标和调节剂、G2/M 阻滞以及细胞增殖和肿瘤生长受损。对人类肺腺癌的分析证实了该途径在 EGFR 突变型肿瘤中的激活，并表明该途径的活性与肿瘤分期、组织学分级、转移、治疗后复发和预后不良相关。
