Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers.

中文翻译：

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核PTEN保护前mRNA剪接以连接高尔基体，从而具有抑制肿瘤的作用。

前mRNA选择性剪接（AS）的失调与癌症密切相关。但是，AS与经典致癌基因/肿瘤抑制因子之间的关系尚不清楚。在这里，我们表明删除肿瘤抑制因子PTEN可以以磷酸酶非依赖性方式改变pre-mRNA剪接，并通过RNA测序鉴定293T细胞中262个PTEN调节的AS事件，这与癌症患者的预后明显差有关。基于这些发现，我们报告核PTEN与剪接机制剪接体相互作用，以调节其组装和前mRNA剪接。我们还在GOLGA2转录物中发现了一个新的外显子2b，该外显子排除通过促进戏剧性的高尔基体延伸和分泌，促进了PTEN敲低诱导的肿瘤发生，