The Deubiquitinase USP13 Regulates PTEN Protein Stability

The tumor suppressor PTEN is commonly mutated or deleted in human tumors, including breast cancer, but can also be downregulated at the protein level, indicating that posttranslational mechanisms also modulate its expression and function. Indeed, recent studies have shown that ubiquitin ligases and the deubiquitinating enzyme (DUB) ubiquitin specific peptidase (USP) 7 regulate PTEN proteasomal degradation and subcellular localization, respectively; however, it remains unclear which DUBs promote PTEN protein stability. Among a panel of 30 DUBs, Zhang and colleagues identified five DUBs that interacted with PTEN, including USP7 and USP13; of these, only USP13 directly interacted with PTEN via its phosphatase domain, resulting in increased PTEN protein expression and reduced downstream phosphorylation of AKT, forkhead box O1 (FOXO1), and FOXO3 in human breast cancer cells. USP13-mediated regulation of PTEN protein was dependent on the catalytic activity of USP13, which triggered PTEN deubiquitination and stabilized PTEN protein without affecting its subcellular localization. Depletion of USP13 augmented cell proliferation and anchorage-independent growth, stimulated glucose uptake and glycolysis, and enhanced xenograft tumor growth via downregulation of PTEN expression and subsequent induction of AKT signaling. In contrast, USP13 overexpression suppressed cell proliferation and tumor growth and impaired glucose uptake in PTEN-expressing but not PTEN-deficient breast cancer cells, further supporting a tumor-suppressive function for USP13 via positive regulation of PTEN protein stability. Moreover, decreased expression of USP13 protein was positively correlated with PTEN protein downregulation in a panel of human breast cancer samples. These findings identify USP13 as a critical posttranslational regulator of PTEN and suggest that USP13 loss may drive PTEN inactivation and tumorigenesis in a large subset of patients with breast cancer.

Zhang J, Zhang P, Wei Y, Piao H, Wang W, Maddika S, et al. Deubiquitylation and stabilization of PTEN by USP13. Nat Cell Biol 2013;15:1486–94.

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