CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
Qin, Dongjun1; Wang, Weiwei1; Lei, Hu1; Luo, Hao1; Cai, Haiyan1; Tang, Caixia1; Wu, Yunzhao1; Wang, Yingying2; Jin, Jin1; Xiao, Weilie3; Wang, Tongdan1; Ma, Chunmin1; Xu, Hanzhang1; Zhang, Jinfu1; Gao, Fenghou2; Wu, Ying-Li1
Source PublicationOncotarget
AbstractDeubiquitinating 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 a, beta-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.
KeywordCddo-me Ovarian Cancer Usp7 Cetsa Deubiquitinating Enzymes
Indexed BySCI
WOS IDWOS:000389633400061
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Cited Times:41[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Affiliation1.Shanghai Jiao Tong Univ, Key Lab Cell Differentiat & Apoptosis,Sch Med, Hongqiao Int Inst Med,Shanghai Tongren Hosp,Fac B, Chem Biol Div,Shanghai Univ E Inst,Chinese Minist, Shanghai, Peoples R China
2.Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Inst Oncol, Shanghai, Peoples R China
3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China
Recommended Citation
GB/T 7714
Qin, Dongjun,Wang, Weiwei,Lei, Hu,et al. CDDO-Me reveals USP7 as a novel target in ovarian cancer cells[J]. Oncotarget,2016,7(47):77096-77109.
APA Qin, Dongjun.,Wang, Weiwei.,Lei, Hu.,Luo, Hao.,Cai, Haiyan.,...&Wu, Ying-Li.(2016).CDDO-Me reveals USP7 as a novel target in ovarian cancer cells.Oncotarget,7(47),77096-77109.
MLA Qin, Dongjun,et al."CDDO-Me reveals USP7 as a novel target in ovarian cancer cells".Oncotarget 7.47(2016):77096-77109.
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