Targeting glioma stem cells through combined BMI1 and EZH2 inhibition

doi:10.1038/nm.4415

科研成果详情

题名	Targeting glioma stem cells through combined BMI1 and EZH2 inhibition
作者	Jin, Xun 1,2,3; Kim, Leo J.Y.1,4,5,6; Wu, Qiulian 1,6; Wallace, Lisa C.1; Prager, Briana C.1,4,5,6,7; Sanvoranart, Tanwarat 1; Gimple, Ryan C.1,4,5,6; Wang, Xiuxing 1,6; Mack, Stephen C.1,8; Miller, Tyler E.1,4,5; Huang, Ping 1; Valentim, Claudia L.1; Zhou, Qi-Gang 1; Barnholtz-Sloan, Jill S.9; Bao, Shideng 1,7,9; Sloan, Andrew E.9,10; Rich, Jeremy N.1,6,7,9
发表日期	2017-11
发表期刊	NATURE MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
其他关键词	TUMOR-INITIATING CELLS ; HUMAN GLIOBLASTOMA ; RADIATION RESPONSE ; GENE-EXPRESSION ; DNA-DAMAGE ; DIFFERENTIATION ; TUMORIGENICITY ; METHYLATION ; POLYCOMB ; DRUG
摘要	Glioblastomas are lethal cancers defined by angiogenesis and pseudopalisading necrosis. Here, we demonstrate that these histological features are associated with distinct transcriptional programs, with vascular regions showing a proneural profile, and hypoxic regions showing a mesenchymal pattern. As these regions harbor glioma stem cells (GSCs), we investigated the epigenetic regulation of these two niches. Proneural, perivascular GSCs activated EZH2, whereas mesenchymal GSCs in hypoxic regions expressed BMI1 protein, which promoted cellular survival under stress due to downregulation of the E3 ligase RNF144A. Using both genetic and pharmacologic inhibition, we found that proneural GSCs are preferentially sensitive to EZH2 disruption, whereas mesenchymal GSCs are more sensitive to BMI1 inhibition. Given that glioblastomas contain both proneural and mesenchymal GSCs, combined EZH2 and BMI1 targeting proved more effective than either agent alone both in culture and in vivo, suggesting that strategies that simultaneously target multiple epigenetic regulators within glioblastomas may be effective in overcoming therapy resistance caused by intratumoral heterogeneity.
资助项目	National Institutes of Health grantsUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [CA203101, CA183510, CA217065, CA217066, CA043703, CA169117, CA184090, NS091080, NS099175, CA197718, CA154130, CA171652, NS087913, NS089272]; Kimble Family Foundation; Ferry Foundation; Jerry Kaufman GBM Research Fund [CA217956]; General Program of the National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81572891]; Canadian Institutes of Health Research Banting FellowshipCanadian Institutes of Health Research (CIHR); NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [F30CA217065, R01CA184090, R35CA197718, R01CA154130, F30CA217066, R01CA171652, F30CA203101, F30CA183510, R01CA169117] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [T32GM007250] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS099175, R01NS087913, R01NS103434, R01NS089272, R01NS091080] Funding Source: NIH RePORTER
出版者	NATURE PUBLISHING GROUP
出版地	NEW YORK
ISSN	1078-8956
EISSN	1546-170X
卷号	23 期号:11 页码:1352-+
DOI	10.1038/nm.4415
页数	13
WOS类目	Biochemistry & Molecular Biology ; Cell Biology ; Medicine, Research & Experimental
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology ; Research & Experimental Medicine
WOS记录号	WOS:000414548300017
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	29035367
PMC记录号	PMC5679732
SCOPUSEID	2-s2.0-85033237290
CNS重要论文	CNS重要论文
自科自定义期刊分类	T2(A)类
通讯作者地址	[Rich, Jeremy N.]Department of Stem Cell Biology and Regenerative Medicine,Lerner Research Institute,Cleveland Clinic,Cleveland,United States
Scopus学科分类	Biochemistry, Genetics and Molecular Biology (all)
TOP期刊	TOP期刊
引用统计	被引频次：192[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/20456
专题	附属第一医院
通讯作者	Rich, Jeremy N.
作者单位	1.Department of Stem Cell Biology and Regenerative Medicine,Lerner Research Institute,Cleveland Clinic,Cleveland,United States; 2.Tianjin Medical University,Cancer Institute and Hospital,Tianjin,China; 3.First Affiliated Hospital,Wenzhou Medical University,Wenzhou, Zhejiang,China; 4.Department of Pathology,Case Western Reserve University,Cleveland,United States; 5.Medical Scientist Training Program,School of Medicine,Case Western Reserve University,Cleveland,United States; 6.Division of Regenerative Medicine,Department of Medicine,University of San Diego,San Diego,United States; 7.Cleveland Clinic,Lerner College of Medicine,Case Western Reserve University,Cleveland,United States; 8.Department of Pediatrics,Division of Pediatric Hematology and Oncology,Baylor College of Medicine,Houston,United States; 9.Case Comprehensive Cancer Center,Case Western Reserve University,School of Medicine,Cleveland,United States; 10.Department of Neurological Surgery,University Hospitals,Cleveland Medical Center,Cleveland,United States
第一作者单位	附属第一医院
推荐引用方式 GB/T 7714	Jin, Xun,Kim, Leo J.Y.,Wu, Qiulian,et al. Targeting glioma stem cells through combined BMI1 and EZH2 inhibition[J]. NATURE MEDICINE,2017,23(11):1352-+.
APA	Jin, Xun., Kim, Leo J.Y.., Wu, Qiulian., Wallace, Lisa C.., Prager, Briana C.., ... & Rich, Jeremy N.. (2017). Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. NATURE MEDICINE, 23(11), 1352-+.
MLA	Jin, Xun,et al."Targeting glioma stem cells through combined BMI1 and EZH2 inhibition".NATURE MEDICINE 23.11(2017):1352-+.