AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition

doi:10.1038/s41401-019-0248-2

	AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition
	Zhang, Kai-li 1,2; Shen, Qian-qian 1; Fang, Yan-fen 1; Sun, Yi-ming 1; Ding, Jian 1; Chen, Yi 1
刊名	ACTA PHARMACOLOGICA SINICA
	2019-12-01
卷号	40 期号:12 页码:1587-1595
关键词	PRC2 EZH2-EED AZD9291 miR-34a non-canonical base pairing
ISSN号	1671-4083
DOI	10.1038/s41401-019-0248-2
通讯作者	Ding, Jian(jding@simm.ac.cn) ; Chen, Yi(ychen@simm.ac.cn)
英文摘要	Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.
WOS关键词	HISTONE METHYLTRANSFERASE EZH2 ; CANCER-CELLS ; SOMATIC MUTATIONS ; STEM-CELLS ; PROLIFERATION ; CHEMOSENSITIVITY ; EXPRESSION ; PROSTATE ; BINDING
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000500546400009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281998]
专题	中国科学院上海药物研究所
通讯作者	Ding, Jian; Chen, Yi
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Kai-li,Shen, Qian-qian,Fang, Yan-fen,et al. AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition[J]. ACTA PHARMACOLOGICA SINICA,2019,40(12):1587-1595.
APA	Zhang, Kai-li,Shen, Qian-qian,Fang, Yan-fen,Sun, Yi-ming,Ding, Jian,&Chen, Yi.(2019).AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition.ACTA PHARMACOLOGICA SINICA,40(12),1587-1595.
MLA	Zhang, Kai-li,et al."AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition".ACTA PHARMACOLOGICA SINICA 40.12(2019):1587-1595.