In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis

Qibiao Wu, Yahui Tian, Jian Zhang, Xinyuan Tong, Hsinyi Huang, Shuai Li, Hong Zhao, Ying Tang, Chongze Yuan, Kun Wang, Zhaoyuan Fang, Lei Gao, Xin Hu, Fuming Li, Zhen Qin, Shun Yao, Ting Chen, Haiquan Chen, Gong Zhang, Wanting LiuYihua Sun, Luonan Chen, Kwok Kin Wong, Kai Ge, Liang Chen, Hongbin Ji

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. 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 KrasG12D/+ 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 KrasG12D/+ 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.

Original languageEnglish (US)
Pages (from-to)E3978-E3986
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number17
DOIs
StatePublished - Apr 24 2018

Keywords

  • CRISPR/Cas9 in vivo knockout
  • EZH2 inhibitor
  • Non-small cell lung cancer
  • Tumor suppressor genes
  • UTX

ASJC Scopus subject areas

  • General

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