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

doi:10.1038/s41375-021-01494-w

HFCAS OpenIR

	Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2
	Yang, Jing 1,2,3,4; Weisberg, Ellen L.5,6; Qi, Shuang1 ; Ni, Wei 5,6; Mei, Husheng 1,7; Wang, Zuowei 1,7; Meng, Chengcheng 5,6; Zhang, Shengzhe 5,6; Hou, Mingqi 1; Qi, Ziping1 ; Wang, Aoli1 ; Jiang, Yunyun 1; Jiang, Zongru 1; Huang, Tao 1; Liu, Qingwang 1; Magin, Robert S.3,4; Doherty, Laura 1,2; Wang, Wenchao1,2 ; Liu, Jing 1; Buhrlage, Sara J.3,4; Liu, Qingsong1,2,7 ; Griffin, James D.5,6
	2022-01-17
发表期刊	LEUKEMIA
ISSN	0887-6924
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)
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.
DOI	10.1038/s41375-021-01494-w
关键词[WOS]	PROSTATE-CANCER CELLS ; GROUP PROTEIN EZH2 ; SOMATIC MUTATIONS ; LYSINE 27 ; POLYCOMB ; METHYLATION ; DEGRADATION ; UBIQUITINATION ; METASTASIS ; PROGNOSIS
收录类别	SCI
语种	英语
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]
项目资助者	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
WOS研究方向	Oncology ; Hematology
WOS类目	Oncology ; Hematology
WOS记录号	WOS:000743022300001
出版者	SPRINGERNATURE
引用统计	被引频次：7[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.hfcas.ac.cn:8080/handle/334002/127128
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.Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Anhui Prov Key Lab Med Phys & Technol, Hefei 230031, Peoples R China 2.Chinese Acad Sci, Hefei Canc Hosp, Hefei 230031, Peoples R China 3.Harvard Med Sch, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA 4.Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA 5.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA 6.Harvard Med Sch, Dept Med, Boston, MA 02115 USA 7.Univ Sci & Technol China, Hefei 230036, Anhui, 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).