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Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3K alpha inhibitors in oesophageal squamous cell carcinoma

文献类型：期刊论文

作者Xing, Hui4,5; Gao, Mengshi4,5; Wang, Yuxiang5; Zhang, Xu4,5; Shi, Jiajie5; Wang, Xiang5; Liu, Xueling5; Ma, Qingyang3; Kong, Xiangyin3; Yang, Chunhao2
刊名CLINICAL AND TRANSLATIONAL MEDICINE
出版日期2022-05-01
卷号12期号:5页码:17
关键词CDKNIA cell cycle CRISPR-SAM CYH33 ESCC EZH2 PI3K alpha inhibitor resistance
ISSN号2001-1326
DOI10.1002/ctm2.835
通讯作者Ding, Jian(jding@simm.ac.cn) ; Meng, Linghua(lhmeng@simm.ac.cn)
英文摘要Phosphoinositide-3 kinase alpha (PI3K alpha) has been confirmed to be a potential therapeutic target for esophageal squamous cell carcinoma (ESCC), while the potency of PI3K alpha inhibitors is often attenuated by concurrent oncogenic signalling pathways. We performed genome-wide gain-of-function screening with a CRISPR-SAM library and identified enhancer of zeste homolog 2 (EZH2) rendering ESCC cells resistant to the PI3K alpha inhibitor CYH33. Enhanced expression of EZH2 frequently occurs in ESCC and is related to poor prognosis. Overexpression of full-length EZH2 but not methyltransferase-deficient EZH2 conferred resistance to CYH33, while downregulating EZH2 expression restored sensitivity. EZH2 expression was negatively related to the activity of CYH33 against the proliferation of ESCC cell lines and patient-derived cells. Transcriptomic analysis revealed that EZH2 abrogated CYH33-mediated cell cycle regulation. EZH2 epigenetically suppressed the transcription of CDKN1A, promoting RB phosphorylation and cell cycle progression. Concurrently targeting EZH2 significantly potentiated CYH33 to inhibit the growth of ESCC cells and patient-derived xenografts accompanied by enhanced cell cycle arrest. Taken together, our study demonstrated that an EZH2-p21-RB axis remodeled cell cycle regulation and rendered resistance to PI3K alpha inhibitors in ESCC. Simultaneously targeting PI3K alpha and EZH2 may provide an effective strategy for ESCC therapy with high expression of EZH2.
WOS关键词TRANSCRIPTIONAL ACTIVATION ; BREAST-CANCER ; SUNITINIB ; NETWORKS ; KNOCKOUT ; PROMOTES ; PI3K
资助项目National Natural Science Foundation of China[82173832] ; National Natural Science Foundation of China[81973345] ; National Natural Science Foundation of China[82104199] ; National Natural Science Foundation of China[LG202103-02-03] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020111]
WOS研究方向Oncology ; Research & Experimental Medicine
语种英语
WOS记录号WOS:000798914800001
出版者JOHN WILEY & SONS LTD
源URL[http://119.78.100.183/handle/2S10ELR8/301068]  
专题新药研究国家重点实验室
通讯作者Ding, Jian; Meng, Linghua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Key Lab Tissue Microenvironm & Tumor, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Sch Pharmaceut Sci, Beijing, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xing, Hui,Gao, Mengshi,Wang, Yuxiang,et al. Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3K alpha inhibitors in oesophageal squamous cell carcinoma[J]. CLINICAL AND TRANSLATIONAL MEDICINE,2022,12(5):17.
APA Xing, Hui.,Gao, Mengshi.,Wang, Yuxiang.,Zhang, Xu.,Shi, Jiajie.,...&Meng, Linghua.(2022).Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3K alpha inhibitors in oesophageal squamous cell carcinoma.CLINICAL AND TRANSLATIONAL MEDICINE,12(5),17.
MLA Xing, Hui,et al."Genome-wide gain-of-function screening identifies EZH2 mediating resistance to PI3K alpha inhibitors in oesophageal squamous cell carcinoma".CLINICAL AND TRANSLATIONAL MEDICINE 12.5(2022):17.

入库方式： OAI收割

来源：上海药物研究所

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