Nuclear PTEN safeguards pre-mRNA splicing to link Golgi extension and secretion for its tumor suppressive role

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. Herein we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in its phosphatase-independent manner, and identifyied 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. Especially, the exon-2b exclusion of GOLGA2 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. Given that many cancers lack PTEN expression, our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers.