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) |
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Article number | 636 |
Journal | Nature communications |
Volume | 10 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2019 |
Funding
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.
ASJC Scopus subject areas
- General Physics and Astronomy
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology