Title: In Vivo CRISPR Screening Unveils Histone Demethylase UTX as An Important Epigenetic Regulator in Lung Tumorigenesis
Authors: Wu, QB; Tian, YH; Zhang, J; Tong, XY; Huang, H; Li, S; Zhao, H; Tang, Y; Yuan, CZ; Wang, K; Fang, ZY; Gao, L; Hu, X; Li, FM; Qin, Z; Yao, S; Chen, T; Chen, HQ; Zhang, G; Liu, WT; Sun, YH; Chen, LN; Wong, KK; Ge, K; Chen, L; Ji, HB
Author Full Names: Wu, Qibiao; Tian, Yahui; Zhang, Jian; Tong, Xinyuan; Huang, Hsinyi; Li, Shuai; Zhao, Hong; Tang, Ying; Yuan, Chongze; Wang, Kun; Fang, Zhaoyuan; Gao, Lei; Hu, Xin; Li, Fuming; Qin, Zhen; Yao, Shun; Chen, Ting; Chen, Haiquan; Zhang, Gong; Liu, Wanting; Sun, Yihua; Chen, Luonan; Wong, Kwok-Kin; Ge, Kai; Chen, Liang; Ji, Hongbin
Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115 (17):E3978-E3986; 10.1073/pnas.1716589115 APR 24 2018
Language: English
Abstract: 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.
ISSN: 0027-8424
IDS Number: GD7MZ
Unique ID: WOS:000430697500017
PubMed ID: 29632194