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

doi:10.1038/s41467-019-08481-x

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

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55 Scopus citations

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 language	English (US)
Article number	636
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08481-x
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Park, M. K., Yao, Y., Xia, W., Setijono, S. R., Kim, J. H., Vila, I. K., Chiu, H. H., Wu, Y., Billalabeitia, E. G., Lee, M. G., Kalb, R. G., Hung, M. C., Pandolfi, P. P., Song, S. J., & Song, M. S. (2019). PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression. Nature communications, 10(1), Article 636. https://doi.org/10.1038/s41467-019-08481-x

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title = "PTEN self-regulates through USP11 via the PI3K-FOXO pathway to stabilize tumor suppression",

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.",

author = "Park, {Mi Kyung} and Yixin Yao and Weiya Xia and Setijono, {Stephanie Rebecca} and Kim, {Jae Hwan} and Vila, {Isabelle K.} and Chiu, {Hui Hsuan} and Yun Wu and Billalabeitia, {Enrique Gonz{\'a}lez} and Lee, {Min Gyu} and Kalb, {Robert G.} and Hung, {Mien Chie} and Pandolfi, {Pier Paolo} and Song, {Su Jung} and Song, {Min Sup}",

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doi = "10.1038/s41467-019-08481-x",

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AU - Yao, Yixin

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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

PY - 2019/12/1

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N2 - 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.

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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