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

doi:10.18632/oncotarget.12801

	CDDO-Me reveals USP7 as a novel target in ovarian cancer cells
	Qin, Dongjun 1; Wang, Weiwei 1; Lei, Hu 1; Luo, Hao 1; Cai, Haiyan 1; Tang, Caixia 1; Wu, Yunzhao 1; Wang, Yingying 2; Jin, Jin 1; Xiao, Weilie 3; Wang, Tongdan 1; Ma, Chunmin 1; Xu, Hanzhang 1; Zhang, Jinfu 1; Gao, Fenghou 2; Wu, Ying-Li 1
	2016-11-22
发表期刊	Oncotarget
卷号	7 期号:47 页码:77096-77109
摘要	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 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.
关键词	Cddo-me Ovarian Cancer Usp7 Cetsa Deubiquitinating Enzymes
DOI	10.18632/oncotarget.12801
收录类别	SCI
语种	英语
WOS记录号	WOS:000389633400061
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/33773
专题	植物化学与西部植物资源持续利用国家重点实验室
作者单位	1.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
推荐引用方式 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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