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 Gordon 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 Gordon Kalb, Mien Chie Hung, Pier Paolo Pandolfi, Su Jung Song, Min Sup Song

Neurology

Research output: Contribution to journal › Article › peer-review

13 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

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

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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), [636]. https://doi.org/10.1038/s41467-019-08481-x

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 Gordon ; 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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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 Gordon} and Hung, {Mien Chie} and Pandolfi, {Pier Paolo} and Song, {Su Jung} and Song, {Min Sup}",

note = "Funding Information: We thank L.C. Cantley and M. Serrano for providing reagents and H.K. Lin, D. Sar-bassov, A. Sahin, and C. Logothetis for their advice and critical discussion. We are grateful to T. Garvey for the critical editing of the manuscript. We are thankful to U. Ala for the technical support in cancer biostatistical analysis. We thank J.P. Hwang, C.C. Yeh, and D.H. Agulla for the technical assistance. This work was supported by a Soon-chunhyang University Research Fund to S.J. Song and a National Institutes of Health grant (CA196740) to M.S. Song.",

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

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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 Gordon; Hung, Mien Chie; Pandolfi, Pier Paolo; Song, Su Jung; Song, Min Sup.

In: Nature communications, Vol. 10, No. 1, 636, 01.12.2019.

Research output: Contribution to journal › Article › peer-review

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AU - Park, Mi Kyung

AU - Yao, Yixin

AU - Xia, Weiya

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 Gordon

AU - Hung, Mien Chie

AU - Pandolfi, Pier Paolo

AU - Song, Su Jung

AU - Song, Min Sup

N1 - Funding Information: We thank L.C. Cantley and M. Serrano for providing reagents and H.K. Lin, D. Sar-bassov, A. Sahin, and C. Logothetis for their advice and critical discussion. We are grateful to T. Garvey for the critical editing of the manuscript. We are thankful to U. Ala for the technical support in cancer biostatistical analysis. We thank J.P. Hwang, C.C. Yeh, and D.H. Agulla for the technical assistance. This work was supported by a Soon-chunhyang University Research Fund to S.J. Song and a National Institutes of Health grant (CA196740) to M.S. Song.

PY - 2019/12/1

Y1 - 2019/12/1

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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