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CDDO-Me reveals USP7 as a novel target in ovarian cancer cells

Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me...

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Autores principales: Qin, Dongjun, Wang, Weiwei, Lei, Hu, Luo, Hao, Cai, Haiyan, Tang, Caixia, Wu, Yunzhao, Wang, Yingying, Jin, Jin, Xiao, Weilie, Wang, Tongdan, Ma, Chunmin, Xu, Hanzhang, Zhang, Jinfu, Gao, Fenghou, Wu, Ying-Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363571/
https://www.ncbi.nlm.nih.gov/pubmed/27780924
http://dx.doi.org/10.18632/oncotarget.12801
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author Qin, Dongjun
Wang, Weiwei
Lei, Hu
Luo, Hao
Cai, Haiyan
Tang, Caixia
Wu, Yunzhao
Wang, Yingying
Jin, Jin
Xiao, Weilie
Wang, Tongdan
Ma, Chunmin
Xu, Hanzhang
Zhang, Jinfu
Gao, Fenghou
Wu, Ying-Li
author_facet Qin, Dongjun
Wang, Weiwei
Lei, Hu
Luo, Hao
Cai, Haiyan
Tang, Caixia
Wu, Yunzhao
Wang, Yingying
Jin, Jin
Xiao, Weilie
Wang, Tongdan
Ma, Chunmin
Xu, Hanzhang
Zhang, Jinfu
Gao, Fenghou
Wu, Ying-Li
author_sort Qin, Dongjun
collection PubMed
description Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones. Molecular docking studies showed that CDDO-Me fits well in the ubiquitin carboxyl terminus-binding pocket on USP7. Given that CDDO-Me is known to be effective against ovarian cancer cells, we speculated that CDDO-Me may target USP7 in ovarian cancer cells. We demonstrated that ovarian cancer cells have higher USP7 expression than their normal counterparts. Knockdown of USP7 inhibits the proliferation of ovarian cancer cells both in vitro and in vivo. Using the cellular thermal shift assay and the drug affinity responsive target stability assay, we further demonstrated that CDDO-Me directly binds to USP7 in cells, which leads to the decrease of its substrates such as MDM2, MDMX and UHRF1. CDDO-Me suppresses ovarian cancer tumor growth in an xenograft model. In conclusion, we demonstrate that USP7 is a novel target of ovarian cancer cells; targeting USP7 may contribute to the anti-cancer effect of CDDO-Me. The development of novel USP7 selective compounds based on the CDDO-Me-scaffold warrants further investigation.
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spelling pubmed-53635712017-03-29 CDDO-Me reveals USP7 as a novel target in ovarian cancer cells Qin, Dongjun Wang, Weiwei Lei, Hu Luo, Hao Cai, Haiyan Tang, Caixia Wu, Yunzhao Wang, Yingying Jin, Jin Xiao, Weilie Wang, Tongdan Ma, Chunmin Xu, Hanzhang Zhang, Jinfu Gao, Fenghou Wu, Ying-Li Oncotarget Research Paper Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones. Molecular docking studies showed that CDDO-Me fits well in the ubiquitin carboxyl terminus-binding pocket on USP7. Given that CDDO-Me is known to be effective against ovarian cancer cells, we speculated that CDDO-Me may target USP7 in ovarian cancer cells. We demonstrated that ovarian cancer cells have higher USP7 expression than their normal counterparts. Knockdown of USP7 inhibits the proliferation of ovarian cancer cells both in vitro and in vivo. Using the cellular thermal shift assay and the drug affinity responsive target stability assay, we further demonstrated that CDDO-Me directly binds to USP7 in cells, which leads to the decrease of its substrates such as MDM2, MDMX and UHRF1. CDDO-Me suppresses ovarian cancer tumor growth in an xenograft model. In conclusion, we demonstrate that USP7 is a novel target of ovarian cancer cells; targeting USP7 may contribute to the anti-cancer effect of CDDO-Me. The development of novel USP7 selective compounds based on the CDDO-Me-scaffold warrants further investigation. Impact Journals LLC 2016-10-21 /pmc/articles/PMC5363571/ /pubmed/27780924 http://dx.doi.org/10.18632/oncotarget.12801 Text en Copyright: © 2016 Qin et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Qin, Dongjun
Wang, Weiwei
Lei, Hu
Luo, Hao
Cai, Haiyan
Tang, Caixia
Wu, Yunzhao
Wang, Yingying
Jin, Jin
Xiao, Weilie
Wang, Tongdan
Ma, Chunmin
Xu, Hanzhang
Zhang, Jinfu
Gao, Fenghou
Wu, Ying-Li
CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
title CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
title_full CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
title_fullStr CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
title_full_unstemmed CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
title_short CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
title_sort cddo-me reveals usp7 as a novel target in ovarian cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363571/
https://www.ncbi.nlm.nih.gov/pubmed/27780924
http://dx.doi.org/10.18632/oncotarget.12801
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