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

Shao-Ming Shen1, Yan Ji2, Cheng Zhang3

  • 1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China. smshen01@sibs.ac.cn.

Nature Communications
|June 21, 2018
PubMed

Insights

Tumor suppressor PTEN deletion alters pre-mRNA splicing, impacting cancer patient outcomes. PTEN interacts with the spliceosome, and its depletion sensitizes cancer cells to secretion inhibitors, offering new therapeutic strategies for PTEN-deficient cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Dysregulation of pre-mRNA alternative splicing (AS) is linked to cancer development.
  • The interplay between AS and tumor suppressors like PTEN is not well understood.

Purpose of the Study:

  • To investigate the role of PTEN in regulating alternative splicing.
  • To identify PTEN-regulated AS events and their association with cancer patient prognosis.
  • To explore the therapeutic potential of targeting pathways affected by PTEN loss.

Main Methods:

  • RNA sequencing to identify PTEN-regulated AS events in 293T cells.
  • Analysis of PTEN-spliceosome interactions.
  • Investigating the functional impact of a novel GOLGA2 exon on tumorigenesis.
  • Assessing sensitivity to secretion inhibitors in PTEN-depleted cancer cells.

Main Results:

  • PTEN deletion alters pre-mRNA splicing independently of its phosphatase activity.
  • 262 PTEN-regulated AS events were identified, correlating with worse cancer patient outcomes.
  • Nuclear PTEN interacts with the spliceosome, influencing its assembly and splicing.
  • A novel GOLGA2 exon (2b) exclusion promotes tumorigenesis via Golgi extension and secretion.
  • PTEN depletion sensitizes cancer cells to secretion inhibitors (brefeldin A, golgicide A).

Conclusions:

  • PTEN plays a crucial role in regulating alternative splicing through spliceosome interaction.
  • PTEN-regulated AS events serve as potential biomarkers for cancer prognosis.
  • Targeting Golgi secretion pathways, potentially combined with PI3K/Akt inhibitors, may be effective for PTEN-deficient cancers.

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