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

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Listed:
  • 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)
    SJTU-SM)

  • Jian-Xiu Yu

    (Shanghai Jiao Tong University School of Medicine (SJTU-SM)
    SJTU-SM)

  • Guo-Qiang Chen

    (Shanghai Jiao Tong University School of Medicine (SJTU-SM))

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.

Suggested Citation

  • 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 & Guo-Qiang Chen, 2018. "Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04760-1
    DOI: 10.1038/s41467-018-04760-1
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    Cited by:

    1. Yan Gu & Yanrong Chen & Lai Wei & Shuang Wu & Kaicheng Shen & Chengxiang Liu & Yan Dong & Yang Zhao & Yue Zhang & Chi Zhang & Wenling Zheng & Jiangyi He & Yunlong Wang & Yifei Li & Xiaoxin Zhao & Hong, 2021. "ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Cunjie Chang & Muthukumar Rajasekaran & Yiting Qiao & Heng Dong & Yu Wang & Hongping Xia & Amudha Deivasigamani & Minjie Wu & Karthik Sekar & Hengjun Gao & Mengqing Sun & Yuqin Niu & Qian Li & Lin Tao, 2022. "The aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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