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

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 <i>Kras</i>^{<i>G12D/</i>+} mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including <i>Utx</i>, <i>Ptip</i>, <i>Acp5</i>, <i>Acacb</i>, and <i>Clu</i>, 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 <i>Utx</i> knockout allele to the <i>Kras</i>^{<i>G12D/</i>+} mouse model, we further find that <i>Utx</i> deletion dramatically promotes lung cancer progression. The tumor-promotive effect of <i>Utx</i> knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the <i>Utx</i>-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.