Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role

Shao-Ming Shen (), Yan Ji, Cheng Zhang, Shuang-Shu Dong, Shuo Yang, Zhong Xiong, Meng-Kai Ge, Yun Yu, Li Xia, Meng Guo, Jin-Ke Cheng, Jun-Ling Liu, Jian-Xiu Yu and Guo-Qiang Chen ()
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Shao-Ming Shen: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Yan Ji: Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM
Cheng Zhang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Shuang-Shu Dong: Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM
Shuo Yang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Zhong Xiong: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Meng-Kai Ge: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Yun Yu: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Li Xia: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Meng Guo: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Jin-Ke Cheng: SJTU-SM
Jun-Ling Liu: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Jian-Xiu Yu: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Guo-Qiang Chen: Shanghai Jiao Tong University School of Medicine (SJTU-SM)

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04760-1

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