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

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 plasma membrane. Poly-ubiquitination 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. Overall design: Profiling of murine dorsolateral prostate cancer tumors in a Hi-Myc genetic background with genetic or pharmacological perturbation of WWP1.