PTEN Self-Regulation via PI3K-FOXO Pathway and USP11 Stabilization

PTEN is a lipid phosphatase that antagonizes the PI3K/AKT pathway and is considered a major dose-dependent tumor suppressor. Therefore, the cellular mechanisms controlling PTEN levels provide potential therapeutic avenues, but these pathways have not been clearly defined. Here, the authors demonstrate that PTEN transcriptionally upregulates the deubiquitinating enzyme USP11 via the PI3K/FOXO pathway, playing an unexpected role in regulating its own stability, and further indicate that this feedforward mechanism is associated with its tumor suppressive effects, as evidenced by the increased susceptibility to PTEN-dependent tumorigenesis, growth, and metastasis in mice lacking Usp11. Notably, USP11 is downregulated in cancer patients and is associated with PTEN expression and FOXO nuclear localization. Therefore, the authors’ findings suggest that the PTEN-PI3K-FOXO-USP11 axis constitutes a regulatory feedforward loop that enhances PTEN stability and tumor suppressive activity.

Loss of USP11 promotes tumor growth and metastasis in TRAMP mice

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