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PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression

Mi Kyung Park1, Yixin Yao1, Weiya Xia1

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Nature Communications
|February 9, 2019
PubMed

Insights

The tumor suppressor PTEN enhances its own stability by upregulating USP11 via the PI3K/FOXO pathway. This feedforward loop is crucial for PTEN’s tumor-suppressive functions and is disrupted in cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • PTEN (phosphatase and tensin homolog) is a critical tumor suppressor antagonizing the PI3K/AKT pathway.
  • Understanding PTEN's regulatory mechanisms is key for developing cancer therapies.
  • Cellular control of PTEN levels remains incompletely defined.

Purpose of the Study:

  • To elucidate the mechanisms controlling PTEN stability and its tumor-suppressive role.
  • To investigate the role of the PI3K/FOXO pathway in PTEN regulation.
  • To identify potential therapeutic targets related to PTEN stability.

Main Methods:

  • Investigated PTEN stability regulation through transcriptional mechanisms.
  • Utilized mouse models lacking Usp11 to assess PTEN-dependent tumor phenotypes.
  • Analyzed PTEN, USP11, and FOXO expression in human cancer patient data.

Main Results:

  • PTEN transcriptionally upregulates the deubiquitinase USP11 via the PI3K/FOXO pathway, creating a positive feedback loop.
  • Mice lacking Usp11 showed increased susceptibility to PTEN-dependent tumor initiation, growth, and metastasis.
  • USP11 downregulation in cancer correlates with reduced PTEN expression and FOXO nuclear localization.

Conclusions:

  • The PTEN-PI3K-FOXO-USP11 pathway forms a feedforward loop enhancing PTEN stability and tumor suppressive activity.
  • This regulatory loop is vital for PTEN's function and is compromised in cancer.
  • Targeting this loop may offer novel therapeutic strategies for PTEN-deficient cancers.

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