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

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  • Mi Kyung Park

    (The University of Texas MD Anderson Cancer Center)

  • Yixin Yao

    (The University of Texas MD Anderson Cancer Center)

  • Weiya Xia

    (The University of Texas MD Anderson Cancer Center)

  • Stephanie Rebecca Setijono

    (Soonchunhyang University)

  • Jae Hwan Kim

    (The University of Texas MD Anderson Cancer Center
    Seoul National University College of Medicine)

  • Isabelle K. Vila

    (The University of Texas MD Anderson Cancer Center)

  • Hui-Hsuan Chiu

    (The University of Texas MD Anderson Cancer Center)

  • Yun Wu

    (The University of Texas MD Anderson Cancer Center)

  • Enrique González Billalabeitia

    (Hospital Universitario Morales Meseguer-IMIB, Universidad Católica San Antonio de Murcia-UCAM)

  • Min Gyu Lee

    (The University of Texas MD Anderson Cancer Center)

  • Robert G. Kalb

    (Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania)

  • Mien-Chie Hung

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    China Medical University)

  • Pier Paolo Pandolfi

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Su Jung Song

    (Soonchunhyang University)

  • Min Sup Song

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

Abstract

PTEN is a lipid phosphatase that antagonizes the PI3K/AKT pathway and is recognized as a major dose-dependent tumor suppressor. The cellular mechanisms that control PTEN levels therefore offer potential routes to therapy, but these are as yet poorly defined. Here we demonstrate that PTEN plays an unexpected role in regulating its own stability through the transcriptional upregulation of the deubiquitinase USP11 by the PI3K/FOXO pathway, and further show that this feedforward mechanism is implicated in its tumor-suppressive role, as mice lacking Usp11 display increased susceptibility to PTEN-dependent tumor initiation, growth and metastasis. Notably, USP11 is downregulated in cancer patients, and correlates with PTEN expression and FOXO nuclear localization. Our findings therefore demonstrate that PTEN-PI3K-FOXO-USP11 constitute the regulatory feedforward loop that improves the stability and tumor suppressive activity of PTEN.

Suggested Citation

  • Mi Kyung Park & Yixin Yao & Weiya Xia & Stephanie Rebecca Setijono & Jae Hwan Kim & Isabelle K. Vila & Hui-Hsuan Chiu & Yun Wu & Enrique González Billalabeitia & Min Gyu Lee & Robert G. Kalb & Mien-Ch, 2019. "PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08481-x
    DOI: 10.1038/s41467-019-08481-x
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