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, Min Sup Song

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Number of pages1
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Feb 7 2019

Fingerprint

Phosphatidylinositol 3-Kinases
Tumors
tumors
retarding
Neoplasms
suppressors
phosphatases
Level control
metastasis
Phosphoric Monoester Hydrolases
mice
lipids
therapy
cancer
Display devices
routes
magnetic permeability
Lipids
Up-Regulation
Down-Regulation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression. / Park, Mi Kyung; Yao, Yixin; Xia, Weiya; Setijono, Stephanie Rebecca; Kim, Jae Hwan; Vila, Isabelle K.; Chiu, Hui Hsuan; Wu, Yun; Billalabeitia, Enrique González; Lee, Min Gyu; Kalb, Robert G.; Hung, Mien Chie; Pandolfi, Pier Paolo; Song, Su Jung; Song, Min Sup.

In: Nature communications, Vol. 10, No. 1, 07.02.2019.

Research output: Contribution to journalArticle

Park, Mi Kyung ; Yao, Yixin ; Xia, Weiya ; Setijono, Stephanie Rebecca ; Kim, Jae Hwan ; Vila, Isabelle K. ; Chiu, Hui Hsuan ; Wu, Yun ; Billalabeitia, Enrique González ; Lee, Min Gyu ; Kalb, Robert G. ; Hung, Mien Chie ; Pandolfi, Pier Paolo ; Song, Su Jung ; Song, Min Sup. / PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
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AU - Setijono, Stephanie Rebecca

AU - Kim, Jae Hwan

AU - Vila, Isabelle K.

AU - Chiu, Hui Hsuan

AU - Wu, Yun

AU - Billalabeitia, Enrique González

AU - Lee, Min Gyu

AU - Kalb, Robert G.

AU - Hung, Mien Chie

AU - Pandolfi, Pier Paolo

AU - Song, Su Jung

AU - Song, Min Sup

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AB - 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.

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