Lee YR1,2, Chen M1,2, Lee JD#1,2, Zhang J#3, Lin SY#4, Fu TM5,6, Chen H7,8, Ishikawa T1,2, Chiang SY4,9, Katon J1,2, Zhang Y1,2, Shulga YV1,2, Bester AC1,2, Fung J1,2, Monteleone E1,2,10, Wan L3,11, Shen C5,6, Hsu CH7,8,12, Papa A13, Clohessy JG1,2,14, Teruya-Feldstein J15, Jain S16, Wu H5,6, Matesic L17, Chen RH4,9, Wei W3, Pandolfi PP18,2
Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.