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Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway

Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway

Science. 2019 May 17;364(6441). pii: eaau0159.
doi: 10.1126/science.aau0159

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Lee YR1,2Chen M1,2Lee JD#1,2Zhang J#3Lin SY#4Fu TM5,6Chen H7,8Ishikawa T1,2Chiang SY4,9Katon J1,2Zhang Y1,2Shulga YV1,2Bester AC1,2Fung J1,2Monteleone E1,2,10Wan L3,11Shen C5,6Hsu CH7,8,12Papa A13Clohessy JG1,2,14Teruya-Feldstein J15Jain S16Wu H5,6Matesic L17Chen RH4,9Wei W3Pandolfi PP18,2

Abstract

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.