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Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors

文献类型：期刊论文

作者Huang, Xun2; Yan, Juan1,2; Zhang, Min1,3; Wang, Yafang2; Chen, Yi2; Fu, Xuhong2; Wei, Rongrui2; Zheng, Xing-ling1,2; Liu, Zhiwei1,3; Zhang, Xiong2
刊名CELL
出版日期2018-09-20
卷号175期号:1页码:186-+
ISSN号0092-8674
DOI10.1016/j.cell.2018.08.058
文献子类Article
英文摘要Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.
WOS关键词NERVE SHEATH TUMORS ; SOMATIC MUTATIONS ; EZH2 INHIBITION ; TRANSCRIPTIONAL REGULATION ; H3K27 ACETYLATION ; STEM-CELLS ; CANCER ; EXPRESSION ; REVEALS ; ERK1
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12000000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020326] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050101] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Natural Science Foundation of China for Innovation Research Group[81321092] ; National Basic Research Program of China (973 Program)[2014CBA02004] ; Natural Science Foundation of China[91229205] ; Natural Science Foundation of China[91753203] ; Natural Science Foundation of China[81872888] ; Special Project on Precision Medicine under the National Key RD Program[SQ2017YFSF090210]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
出版者CELL PRESS
WOS记录号WOS:000445120000023
源URL[http://119.78.100.183/handle/2S10ELR8/279575]  
专题化学蛋白质组学研究中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药理学第一研究室
通讯作者Tan, Minjia; Ding, Jian; Geng, Meiyu
作者单位1.Univ Chinese Acad Sci, Beijing, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Chem Prote Ctr, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Huang, Xun,Yan, Juan,Zhang, Min,et al. Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors[J]. CELL,2018,175(1):186-+.
APA Huang, Xun.,Yan, Juan.,Zhang, Min.,Wang, Yafang.,Chen, Yi.,...&Geng, Meiyu.(2018).Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors.CELL,175(1),186-+.
MLA Huang, Xun,et al."Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors".CELL 175.1(2018):186-+.

入库方式： OAI收割

来源：上海药物研究所

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