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 the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing...

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Published in:	Science (American Association for the Advancement of Science) Vol. 364; no. 6441
Main Authors:	Lee, Yu-Ru, Chen, Ming, Lee, Jonathan D, Zhang, Jinfang, Lin, Shu-Yu, Fu, Tian-Min, Chen, Hao, Ishikawa, Tomoki, Chiang, Shang-Yin, Katon, Jesse, Zhang, Yang, Shulga, Yulia V, Bester, Assaf C, Fung, Jacqueline, Monteleone, Emanuele, Wan, Lixin, Shen, Chen, Hsu, Chih-Hung, Papa, Antonella, Clohessy, John G, Teruya-Feldstein, Julie, Jain, Suresh, Wu, Hao, Matesic, Lydia, Chen, Ruey-Hwa, Wei, Wenyi, Pandolfi, Pier Paolo
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 17-05-2019
Subjects:	1-Phosphatidylinositol 3-kinase Ablation Activation AKT protein Animal models Anticarcinogenic Agents - pharmacology Anticarcinogenic Agents - therapeutic use Cancer Cancer therapies Carcinogenesis - drug effects Computer simulation Deactivation Depletion Dimerization Dimers Evolutionary conservation Fibroblasts Genetic transformation HEK293 Cells Humans Immunoprecipitation Inactivation Indole-3-carbinol Indoles - pharmacology Indoles - therapeutic use Inhibition Inhibitors Kinases Localization Male Mass spectrometry Mass spectroscopy Mice Molecular modelling Mutation Myc protein Neoplasia Neoplasms - drug therapy Neoplasms - metabolism Pharmacology Phosphatase Prostate cancer Protein Multimerization Proteins Proto-Oncogene Proteins c-myc - antagonists & inhibitors Proto-Oncogene Proteins c-myc - genetics PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism PTEN protein Recruitment Regulators Senescence Signal transduction Signaling Strategy Suppressors Transcription Tumor suppressor genes Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumorigenesis Tumors Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - antagonists & inhibitors Ubiquitin-Protein Ligases - genetics Ubiquitination - drug effects Vegetables
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Summary:	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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: Y.-R.L., M.C., J.D.L., J.Z., S.-Y.L., T.-M.F., H.C., T.I., S.-Y.C., J.K., Y.Z., Y.V.S., A.C.B., J.F., E.M., L.W., C.S., C.-H.H., A.P., J.T.-F., and S.J. performed the experiments. Y.-R.L., M.C., J.G.C., R.-H.C., W.W., and P.P.P. conceived and designed the experiments. R.-H.C., W.W., and P.P.P. supervised the study. S.-Y.L. and S.-Y.C. performed the NanoLC-MS/MS analysis. J.D.L., T.I., and E.M. performed all bioinformatic analyses. J.D.L. analyzed all the RNA-seq data. T.-M.F., H.C., C.-H.H., and C.S. purified proteins and performed MST analyses. T.-M.F. and H.W. performed in silico molecular modeling analyses. J.K. and J.F. performed all the IHC staining. Y.-R.L., M.C., Y.V.S., and J.K. maintained the mice colonies and performed all the mice-related experiments and analyses. Y.Z. and A.C.B. performed CRISPRCas9–mediated deletion of MYC responsive element within WWP1 promoter or deletion of Pten in mouse prostate organoids. E.M. performed qChIP assays. S.J. performed the pharmacokinetic analysis of I3C. L.M. provided us with the Wwp1−/− mice and the paired Wwp1+/+ mice (on a C57/BL6 background). Y.-R.L., M.C., J.D.L., J.Z., S.-Y.L., T.-M.F., H.C., T.I., S.-Y.C., J.K., Y.Z., Y.V.S., A.C.B., J.F., E.M., L.W., C.S., C.-H.H., A.P., J.T.-F., and P.P.P. analyzed the data. Y.-R.L., M.C., J.D.L., J.Z., A.P., R.-H.C., W.W., and P.P.P. wrote the manuscript. All authors critically discussed the results and the manuscript. These authors contributed equally to this work. Present address: Duke Cancer Institute, Duke University, Durham, NC 27710, USA. Present address: Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.aau0159