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

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

Lee YR1,2, Chen M1,2, Lee JD#1,2, Zhang J#3, Lin SY#4, Fu TM5,6, Chen H7,8, Ishikawa T1,2, Chiang SY4,9, Katon J1,2, Zhang Y1,2, Shulga YV1,2, Bester AC1,2, Fung J1,2, Monteleone E1,2,10, Wan L3,11, Shen C5,6, Hsu CH7,8,12, Papa A13, Clohessy JG1,2,14, Teruya-Feldstein J15, Jain S16, Wu H5,6, Matesic L17, Chen RH4,9, Wei W3, Pandolfi PP18,2.

Author information

1
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
3
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
4
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
6
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
7
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
8
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
9
Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
10
Department of Molecular Biotechnology and Health Sciences, and GenoBiToUS, Genomics and Bioinformatics Service, University of Turin, Turin, Italy.
11
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
12
Department of Public Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, Zhejiang, China.
13
Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia.
14
Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
15
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
16
Intonation Research Laboratories, Hyderabad, India.
17
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
18
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA. ppandolf@bidmc.harvard.edu.
#
Contributed equally

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.

Comment in

PMID:
31097636
DOI:
10.1126/science.aau0159

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