期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 17, 页码 E3978-E3986出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716589115
关键词
tumor suppressor genes; CRISPR/Cas9 in vivo knockout; non-small cell lung cancer; UTX; EZH2 inhibitor
资金
- National Basic Research Program of China [2017YFA0505501]
- Chinese Academy of Sciences [XDB19020201]
- National Natural Science Foundation of China [81325015, 81430066, 91731314, 31621003, 31370747, 81402276, 81402371, 81401898, 81402498, 81101583, 81372509]
- Science and Technology Commission of Shanghai Municipality [15XD1504000]
- China Postdoctoral Science Foundation [2015M581673]
- Chinese Academy of Science Taiwan Young Scholar Visiting Program [2015TW1SB0001]
- National Science Foundation [81472606]
- Science and Technology Program of Guangzhou [201803010124]
- National Key R&D Program of China [2016YFC0905500]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK075003] Funding Source: NIH RePORTER
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.
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