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In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis
Wu, Qibiao1; Tian, Yahui2; Zhang, Jian1; Tong, Xinyuan1; Huang, Hsinyi1; Li, Shuai3; Zhao, Hong2; Tang, Ying1; Yuan, Chongze4,5; Wang, Kun6; Fang, Zhaoyuan1; Gao, Lei2; Hu, Xin7,8; Li, Fuming1; Qin, Zhen1; Yao, Shun1; Chen, Ting3; Chen, Haiquan4,5; Zhang, Gong2; Liu, Wanting2; Sun, Yihua4,5; Chen, Luonan1; Wong, Kwok-Kin3; Ge, Kai9; Chen, Liang2; Ji, Hongbin1,10
2018-04-24
发表期刊PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷号115期号:17页码:E3978-E3986
文章类型Article
摘要Lung cancer is the leading cause of cancer-related death world-wide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in a Kras(G12D/+) mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including Utx, Ptip, Acp5, Acacb, and Clu, whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditional Utx knockout allele to the Kras(G12D/+) mouse model, we further find that Utx deletion dramatically promotes lung cancer progression. The tumor-promotive effect of Utx knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the Utx-knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis.
关键词Tumor Suppressor Genes Crispr/cas9 In Vivo Knockout Non-small Cell Lung Cancer Utx Ezh2 Inhibitor
WOS标题词Science & Technology
DOI10.1073/pnas.1716589115
关键词[WOS]LYSINE-4 METHYLTRANSFERASE COMPLEX ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; K-RAS ; CANCER ; ADENOCARCINOMA ; POLYCOMB ; CELLS ; DIFFERENTIATION ; EXPRESSION ; IDENTIFICATION
收录类别SCI
语种英语
项目资助者National Basic Research Program of China(2017YFA0505501) ; Chinese Academy of Sciences(XDB19020201) ; National Natural Science Foundation of China(81325015 ; Science and Technology Commission of Shanghai Municipality(15XD1504000) ; China Postdoctoral Science Foundation(2015M581673) ; Chinese Academy of Science Taiwan Young Scholar Visiting Program(2015TW1SB0001) ; National Science Foundation(81472606) ; Science and Technology Program of Guangzhou(201803010124) ; National Key R&D Program of China(2016YFC0905500) ; 81430066 ; 91731314 ; 31621003 ; 31370747 ; 81402276 ; 81402371 ; 81401898 ; 81402498 ; 81101583 ; 81372509)
WOS研究方向Science & Technology - Other Topics
WOS类目Multidisciplinary Sciences
WOS记录号WOS:000430697500017
引用统计
被引频次:3[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.ia.ac.cn/handle/173211/22040
专题中国科学院分子影像重点实验室
作者单位1.Univ Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Chinese Acad Sci,CAS Ctr Excellence Mol Cell Sci, Innovat Ctr Cell Signaling Network,State Key Lab, Shanghai 200031, Peoples R China
2.Jinan Univ, Inst Life & Hlth Engn, Guangzhou 510632, Guangdong, Peoples R China
3.NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, 550 1St Ave, New York, NY 10016 USA
4.Fudan Univ, Dept Thorac Surg, Shanghai Canc Ctr, Shanghai 200031, Peoples R China
5.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200031, Peoples R China
6.Chinese Acad Sci, Inst Automat, Key Lab Mol Imaging, Beijing 100190, Peoples R China
7.Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA
8.Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA
9.NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA
10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China
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Wu, Qibiao,Tian, Yahui,Zhang, Jian,et al. In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2018,115(17):E3978-E3986.
APA Wu, Qibiao.,Tian, Yahui.,Zhang, Jian.,Tong, Xinyuan.,Huang, Hsinyi.,...&Ji, Hongbin.(2018).In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,115(17),E3978-E3986.
MLA Wu, Qibiao,et al."In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115.17(2018):E3978-E3986.
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