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Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice

文献类型：期刊论文

作者Huang, Qingrong2,3; He, Shan2,3; Huang, Jiefang2,3; Yu, Hongshuang2,3; Jin, Min2,3; Zhang, Yanyun2,3,5,8; He, Shan4; Liu, Yongnian4; Tong, Qing4; Zhang, Yi4
刊名BLOOD
出版日期2017
卷号129期号:20页码:2737-2748
关键词Metabolomics Lipid peroxidation Lipidomics Myocardial infarction Isoprostanes Coronary heart disease (CHD)
ISSN号0006-4971
DOI10.1182/blood-2016-08-735886
文献子类Article
英文摘要Modulating T-cell alloreactivity has been a main strategy to reduce graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Genetic deletion of T-cell Ezh2, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), inhibits GVHD. Therefore, reducing Ezh2-mediated H3K27me3 is thought to be essential for inhibiting GVHD. We tested this hypothesis in mouse GVHD models. Unexpectedly, administration of the Ezh2 inhibitor GSK126, which specifically decreases H3K27me3 without affecting Ezh2 protein, failed to prevent the disease. In contrast, destabilizing T-cell Ezh2 protein by inhibiting Hsp90 using its specific inhibitor AUY922 reduced GVHD in mice undergoing allogeneic HSCT. In vivo administration of AUY922 selectively induced apoptosis of activated T cells and decreased the production of effector cells producing interferon gamma and tumor necrosis factor a, similar to genetic deletion of Ezh2. Introduction of Ezh2 into alloreactive T cells restored their expansion and production of effector cytokines upon AUY922 treatment, suggesting that impaired T-cell alloreactivity by inhibiting Hsp90 is achieved mainly through depleting Ezh2. Mechanistic analysis revealed that the enzymatic SET domain of Ezh2 directly interacted with Hsp90 to prevent Ezh2 from rapid degradation in activated T cells. Importantly, pharmacological inhibition of Hsp90 preserved antileukemia activity of donor T cells, leading to improved overall survival of recipient mice after allogeneic HSCT. Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T-cell responses and an effective target for controlling GVHD.
学科主题Hematology
WOS关键词HISTONE H3 ; CHAPERONE INHIBITORS ; GENE-EXPRESSION ; CANCER CELLS ; TYPE-2 CELLS ; STEM-CELLS ; LYSINE 9 ; METHYLATION ; DIFFERENTIATION ; PLASTICITY
语种英语
WOS记录号WOS:000401523300006
出版者AMER SOC HEMATOLOGY
版本出版稿
源URL[http://202.127.25.144/handle/331004/1052]  
专题中国科学院上海生命科学研究院营养科学研究所
作者单位1.Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA;
2.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai, Peoples R China;
3.Shanghai Jiao Tong Univ, Sch Med, Shanghai 200031, Peoples R China;
4.Temple Univ, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19122 USA;
5.Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Shanghai Inst Immunol, Shanghai, Peoples R China;
6.Univ Penn, Childrens Hosp Philadelphia, Div Endocrinol, Philadelphia, PA 19104 USA;
7.Univ Penn, Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA;
8.Soochow Univ, Inst Translat Med, Childrens Hosp, Dept Hematol, Suzhou, Peoples R China;
9.Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;
10.Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA;
推荐引用方式
GB/T 7714		 Huang, Qingrong,He, Shan,Huang, Jiefang,et al. Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice[J]. BLOOD,2017,129(20):2737-2748.
APA Huang, Qingrong.,He, Shan.,Huang, Jiefang.,Yu, Hongshuang.,Jin, Min.,...&,.(2017).Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice.BLOOD,129(20),2737-2748.
MLA Huang, Qingrong,et al."Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice".BLOOD 129.20(2017):2737-2748.

入库方式： OAI收割

来源：上海营养与健康研究所

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