WWP1 Inhibition Rescues PTEN Tumor-Suppressive Activity

PTEN is among the most frequently altered tumor suppressors in human cancer and functions in a haploinsufficient manner, with partial loss of activity in many tumors. Activation of PTEN function is dependent on its dimerization and localization to the plasma membrane; however, the mechanisms that regulate these processes are not well understood. Lee and colleagues sought to identify upstream regulators of PTEN activity that could be exploited to restore or enhance PTEN function in tumors. Profiling of PTEN interactors in prostate cancer cells identified WW domain–containing E3 ubiquitin protein ligase 1 (WWP1) as one of the strongest PTEN interactors. Functional characterization revealed that WWP1 induced K27-linked polyubiquitination of PTEN at residues K342 and K344. WWP1-mediated PTEN polyubiquitination did not decrease overall PTEN protein levels via proteasomal degradation, but instead suppressed PTEN dimerization and membrane recruitment, thereby antagonizing its tumor-suppressive function as a negative regulator of PI3K/AKT signaling. WWP1 expression was induced by MYC, resulting in impaired PTEN dimerization and membrane accumulation and enhanced AKT activation. WWP1 is frequently coamplified with MYC in a variety of human cancers, and WWP1 expression negatively correlated with membrane-bound PTEN in human prostate cancer cell lines. Consistent with these findings, Wwp1 depletion in a MYC-driven mouse prostate cancer model significantly decreased tumorigenesis, which was associated with increased membrane-bound levels of PTEN and inhibition of PI3K/AKT signaling. In addition, the natural compound indole-3-carbinol (I3C) was found to directly inhibit WWP1 E3 ligase activity and PTEN K27-linked polyubiquitination, and I3C treatment suppressed the growth of MYC-driven prostate organoids and tumors via restoration of PTEN activity. This study identifies WWP1 as a regulator of PTEN and suggests WWP1 inhibition as a potential pharmacologic strategy to reactivate PTEN function in tumors.

Lee Y-R, Chen M, Lee JD, Zhang J, Lin S-Y, Fu T-M, et al. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 2019;364:eaau0159.

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