Cancer genomic studies have provided a comprehensive spectrum of thousands of potentially important genetic alterations of tumor suppressor genes (TSGs). Except for a few well-studied TSGs, most of these genetic aberrations still remain to be functionally validated and characterized.

Given the emergence of a tremendous amount of cancer genomic alterations, traditional methods clearly could not meet the demand. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has been proven to be a powerful genome editing tool in recent years. This type of somatic gene knockout technique makes it feasible to efficiently and systematically identify potential TSGs in vivo.

The research groups led by Dr. JI Hongbin at Shanghai Institute of Biochemistry and Cell Biology of Chinese Academy of Sciences (CAS) and Dr. CHEN Liang at Institute of Life and Health Engineering, Jinan University, provided a systematic CRISPR screening of TSGs in vivo and demonstrated that UTX functions as the important epigenetic regulator in lung tumorigenesis. The findings were published online in PNAS.

In this study, the researchers first generated a list of potential TSG candidates based on integrative bioinformatics analyses. Taking advantage of the CRISPR/Cas9-mediated screening in vivo technique, they identified multiple TSGs including Utx, Ptip, Acp5, Acacb, and Clu for their contribution to lung cancer malignant progression.

They then revealed that all these genes were frequently down-regulated in human lung cancer specimens and significantly associated with lung cancer patient survival. Importantly, conditional knockout of the histone demethylase Utx dramatically accelerated lung tumorigenesis in the Kras^LSL-G12D/+ mouse model.

Further evidence demonstrated that Utx knockout increased H3K27me3 level potentially through EZH2 upregulation. Moreover, the researchers found a treatment strategy for UTX-deficient lung tumors. The EZH2 inhibitor JQEZ5 preferentially suppresses the growth of Utx-knockout lung tumors, providing therapeutic implication for human lung cancer with KRAS mutations exhibiting low UTX level.

This study was supported by the National Basic Research Program of China, Strategic Priority Research Program of CAS, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, China Postdoctoral Science Foundation, etc.