In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis
Menée à l'aide de la technologie CRISPR/Cas9 sur des modèles murins de cancer du poumon, cette étude met en évidence des mécanismes par lesquels le gène UTX exerce une fonction de suppresseur de tumeurs
Tumor suppressor genes (TSGs) play important roles in lung cancer initiation, progression, and even metastasis. Here, we take advantage of the clustered regularly interspaced short palindromic repeats/Cas9-mediated screening in vivo technique to identify multiple tumor suppressor genes contributing to lung cancer malignant progression. Using genetically engineered mouse models, we further confirm the tumor-suppressive role of epigenetic regulator UTX and provide therapeutic implications for UTX-deficient lung tumors. Thus, our work provides a systematic screening of TSGs in vivo and demonstrates UTX functions as the important epigenetic regulator in lung tumorigenesis.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.