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Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2

文献类型：期刊论文

作者Yang, Jing4,5,6,7; Weisberg, Ellen L.2,3; Qi, Shuang7; Ni, Wei2,3; Mei, Husheng1,7; Wang, Zuowei1,7; Meng, Chengcheng2,3; Zhang, Shengzhe2,3; Hou, Mingqi7; Qi, Ziping7
刊名LEUKEMIA
出版日期2022-01-17
ISSN号0887-6924
DOI10.1038/s41375-021-01494-w
通讯作者Buhrlage, Sara J.(saraj_buhrlage@dfci.harvard.edu) ; Liu, Qingsong(qsliu97@hmfl.ac.cn) ; Griffin, James D.(james_griffin@dfci.harvard.edu)
英文摘要Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.
WOS关键词PROSTATE-CANCER CELLS ; GROUP PROTEIN EZH2 ; SOMATIC MUTATIONS ; LYSINE 27 ; POLYCOMB ; METHYLATION ; DEGRADATION ; UBIQUITINATION ; METASTASIS ; PROGNOSIS
资助项目National Natural Science Foundation of China[82104198] ; National Natural Science Foundation of China[81903659] ; National Natural Science Foundation of China[32171479] ; Natural Science Foundation of Anhui Province[1908085MH259] ; Leukemia & Lymphoma Society's New Idea Award ; Claudia Adams Barr Award ; MPN Research Foundation ; Gabrielle's Angel Foundation ; NIH Foundation[CA211681] ; NIH Foundation[5 P50 CA206963-02]
WOS研究方向Oncology ; Hematology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000743022300001
资助机构National Natural Science Foundation of China ; Natural Science Foundation of Anhui Province ; Leukemia & Lymphoma Society's New Idea Award ; Claudia Adams Barr Award ; MPN Research Foundation ; Gabrielle's Angel Foundation ; NIH Foundation
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/127127]  
专题中国科学院合肥物质科学研究院
通讯作者Buhrlage, Sara J.; Liu, Qingsong; Griffin, James D.
作者单位1.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
2.Harvard Med Sch, Dept Med, Boston, MA 02115 USA
3.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
4.Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
5.Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
6.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China
7.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Jing,Weisberg, Ellen L.,Qi, Shuang,et al. Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2[J]. LEUKEMIA,2022.
APA Yang, Jing.,Weisberg, Ellen L..,Qi, Shuang.,Ni, Wei.,Mei, Husheng.,...&Griffin, James D..(2022).Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2.LEUKEMIA.
MLA Yang, Jing,et al."Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2".LEUKEMIA (2022).

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来源：合肥物质科学研究院

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