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Neddylation of PTEN regulates its nuclear import and promotes tumor development

Ping Xie1, Zhiqiang Peng2, Yujiao Chen3

  • 1Department of Cell Biology, The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China. xiep@ccmu.edu.cn.

Cell Research
|December 10, 2020
PubMed

Insights

High glucose induces Nedd8 conjugation to PTEN, promoting its nuclear import and unexpected tumor-promoting functions. Neddylated PTEN enhances cell proliferation and fatty acid synthesis, correlating with poor breast cancer prognosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • PTEN (Phosphatase and tensin homolog) is a crucial tumor suppressor opposing the PI3K/Akt pathway.
  • Nuclear PTEN is traditionally viewed as tumor-suppressive, with its nucleocytoplasmic shuttling regulated by post-translational modifications.
  • The role of PTEN neddylation in cancer biology remains largely unexplored.

Purpose of the Study:

  • To investigate the role of PTEN neddylation under high glucose conditions.
  • To elucidate the impact of neddylated PTEN on cellular functions and its clinical relevance in breast cancer.

Main Methods:

  • Utilized cell culture under high glucose conditions to induce PTEN neddylation.
  • Employed biochemical assays to identify PTEN neddylation sites (Lys197, Lys402) and regulatory enzymes (XIAP, NEDP1).
  • Analyzed the effect of neddylated PTEN on fatty acid synthase (FASN) stability and de novo fatty acid synthesis.
  • Correlated neddylated PTEN levels with clinical data from human breast cancer tissues.

Main Results:

  • High glucose conditions promote PTEN conjugation with Nedd8 (neural precursor cell expressed developmentally down-regulated 8), inducing nuclear import without affecting PTEN stability.
  • Neddylated PTEN accumulates in the nucleus, promoting cell proliferation and metabolism, contrary to the established tumor-suppressive role of PTEN.
  • Nuclear neddylated PTEN dephosphorylates FASN, inhibits its degradation, and enhances de novo fatty acid synthesis.
  • Elevated levels of neddylated PTEN in human breast cancer tissues correlate with tumor progression and poor patient prognosis.

Conclusions:

  • PTEN undergoes Nedd8 conjugation under high glucose, leading to nuclear accumulation and a novel tumor-promoting function.
  • Neddylated PTEN plays a critical role in enhancing fatty acid synthesis, contributing to cancer progression.
  • This study reveals an unexpected oncogenic role for nuclear PTEN in its Nedd8-conjugated form, offering potential therapeutic targets in breast cancer.

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