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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticarcinogenic Agents / pharmacology*
  • Anticarcinogenic Agents / therapeutic use
  • Carcinogenesis / drug effects
  • HEK293 Cells
  • Humans
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Male
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Protein Multimerization
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitination / drug effects

Substances

  • Anticarcinogenic Agents
  • Indoles
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Proteins
  • indole-3-carbinol
  • WWP1 protein, human
  • Ubiquitin-Protein Ligases
  • PTEN Phosphohydrolase
  • PTEN protein, human