title: Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice.
abstract: 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 γ and tumor necrosis factor α, 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.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qingrong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA.
authors.forename: Shan
authors.identifier: 0000-0002-8558-7490
authors.initials: S
authors.lastname: He
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Division of Endocrinology and Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Division of Endocrinology and Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiefang
authors.initials: J
authors.lastname: Huang
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA.
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hongshuang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Hematology, Children's Hospital, Institutes for Translational Medicine, Soochow University, Suzhou, China.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tong
authors.affiliation: Department of Pharmacological Sciences and.|Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Anqi
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Pharmacological Sciences and.|Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hexner
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health, Philadelphia, PA.
authors.forename: Henry
authors.initials: H
authors.lastname: Fung
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY; and.
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA.|Department of Microbiology and Immunology, Temple University, Philadelphia, PA.
authors.forename: Yi
authors.identifier: 0000-0002-3456-2728
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Department of Hematology, Children's Hospital, Institutes for Translational Medicine, Soochow University, Suzhou, China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000737:chemistry / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006657:Histones / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D000072417:Protein Domains; D055550:Protein Stability / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D012118:Resorcinols / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C577920:GSK-2816126; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D007211:Indoles; D007555:Isoxazoles; D015778:Minor Histocompatibility Antigens; D011728:Pyridones; D012118:Resorcinols; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D008239:Lysine