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

Yu Ru Lee, Ming Chen, Jonathan D. Lee, Jinfang Zhang, Shu Yu Lin, Tian Min Fu, Hao Chen, Tomoki Ishikawa, Shang Yin Chiang, Jesse Katon, Yang Zhang, Yulia V. Shulga, Assaf C. Bester, Jacqueline Fung, Emanuele Monteleone, Lixin Wan, Chen Shen, Chih Hung Hsu, Antonella Papa, John G. ClohessyJulie Teruya-Feldstein, Suresh Jain, Hao Wu, Lydia Matesic, Ruey Hwa Chen, Wenyi Wei, Pier Paolo Pandolfi

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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. WWP1 appears 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.

Original languageEnglish
Article numbereaau0159
Number of pages15
JournalScience
Volume364
Issue number6441
DOIs
Publication statusPublished - 17 May 2019

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