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

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-Chie Hung, Pier Paolo Pandolfi, Su Jung Song () and Min Sup Song ()
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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
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08481-x

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