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. Clohessy & 7 others Julie Teruya-Feldstein, Suresh Jain, Hao Wu, Lydia Matesic, Ruey Hwa Chen, Wenyi Wei, Pier Paolo Pandolfi

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

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

Cite this

Lee, Y. R., Chen, M., Lee, J. D., Zhang, J., Lin, S. Y., Fu, T. M., ... Pandolfi, P. P. (2019). Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science, 364(6441), [eaau0159]. https://doi.org/10.1126/science.aau0159
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. / Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. In: Science. 2019 ; Vol. 364, No. 6441.
@article{0b32792e33c346cd84ba3312ba538c6a,
title = "Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway",
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.",
author = "Lee, {Yu Ru} and Ming Chen and Lee, {Jonathan D.} and Jinfang Zhang and Lin, {Shu Yu} and Fu, {Tian Min} and Hao Chen and Tomoki Ishikawa and Chiang, {Shang Yin} and Jesse Katon and Yang Zhang and Shulga, {Yulia V.} and Bester, {Assaf C.} and Jacqueline Fung and Emanuele Monteleone and Lixin Wan and Chen Shen and Hsu, {Chih Hung} and Antonella Papa and Clohessy, {John G.} and Julie Teruya-Feldstein and Suresh Jain and Hao Wu and Lydia Matesic and Chen, {Ruey Hwa} and Wenyi Wei and Pandolfi, {Pier Paolo}",
year = "2019",
month = "5",
day = "17",
doi = "10.1126/science.aau0159",
language = "English",
volume = "364",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "6441",

}

Lee, YR, Chen, M, Lee, JD, Zhang, J, Lin, SY, Fu, TM, Chen, H, Ishikawa, T, Chiang, SY, Katon, J, Zhang, Y, Shulga, YV, Bester, AC, Fung, J, Monteleone, E, Wan, L, Shen, C, Hsu, CH, Papa, A, Clohessy, JG, Teruya-Feldstein, J, Jain, S, Wu, H, Matesic, L, Chen, RH, Wei, W & Pandolfi, PP 2019, 'Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway', Science, vol. 364, no. 6441, eaau0159. https://doi.org/10.1126/science.aau0159

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

In: Science, Vol. 364, No. 6441, eaau0159, 17.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway

AU - Lee, Yu Ru

AU - Chen, Ming

AU - Lee, Jonathan D.

AU - Zhang, Jinfang

AU - Lin, Shu Yu

AU - Fu, Tian Min

AU - Chen, Hao

AU - Ishikawa, Tomoki

AU - Chiang, Shang Yin

AU - Katon, Jesse

AU - Zhang, Yang

AU - Shulga, Yulia V.

AU - Bester, Assaf C.

AU - Fung, Jacqueline

AU - Monteleone, Emanuele

AU - Wan, Lixin

AU - Shen, Chen

AU - Hsu, Chih Hung

AU - Papa, Antonella

AU - Clohessy, John G.

AU - Teruya-Feldstein, Julie

AU - Jain, Suresh

AU - Wu, Hao

AU - Matesic, Lydia

AU - Chen, Ruey Hwa

AU - Wei, Wenyi

AU - Pandolfi, Pier Paolo

PY - 2019/5/17

Y1 - 2019/5/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85066443035&partnerID=8YFLogxK

U2 - 10.1126/science.aau0159

DO - 10.1126/science.aau0159

M3 - Article

VL - 364

JO - Science

JF - Science

SN - 0036-8075

IS - 6441

M1 - eaau0159

ER -