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; Julie Teruya-Feldstein; Suresh Jain; Hao Wu; Lydia Matesic; Ruey Hwa Chen; Wenyi Wei; Pier Paolo Pandolfi

doi:10.1126/science.aau0159

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. ClohessyJulie Teruya-Feldstein, Suresh Jain, Hao Wu, Lydia Matesic, Ruey Hwa Chen, Wenyi Wei, Pier Paolo Pandolfi

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215 Scopus citations

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 language	English
Article number	eaau0159
Journal	Science
Volume	364
Issue number	6441
DOIs	https://doi.org/10.1126/science.aau0159
State	Published - May 17 2019

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Lee, Y. R., Chen, M., Lee, J. D., Zhang, J., Lin, S. Y., Fu, T. M., Chen, H., Ishikawa, T., Chiang, S. Y., Katon, J., Zhang, Y., Shulga, Y. V., Bester, A. C., Fung, J., Monteleone, E., Wan, L., Shen, C., Hsu, C. H., Papa, A., ... Pandolfi, P. P. (2019). Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science, 364(6441), Article eaau0159. https://doi.org/10.1126/science.aau0159

@article{57231bd73e11404996de30b5cdf525e8,

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 = may,

day = "17",

doi = "10.1126/science.aau0159",

language = "English",

volume = "364",

journal = "Science",

issn = "0036-8075",

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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

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.

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U2 - 10.1126/science.aau0159

DO - 10.1126/science.aau0159

M3 - Article

C2 - 31097636

AN - SCOPUS:85066443035

SN - 0036-8075

VL - 364

JO - Science

JF - Science

IS - 6441

M1 - eaau0159

ER -

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

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