Genome-wide identification of transcription factors that are critical to non-small cell lung cancer.
To systematically unveil transcription factors (TFs) that are critical to lung carcinogenesis, here we conducted a genome-wide lethality screening in non-small cell lung cancer (NSCLC) cells and reported that among the 1530 TFs tested, 21 genes were required for NSCLC cell proliferation and were negatively or positively associated with overall survival (OS) of patients with NSCLC. These included 11 potential tumor suppressing genes (AFF3, AhR, AR, CBFA2T3, CHD4, KANK2, NR3C2, PTEN, PRDM16, RB1, and STK11) and 10 potential oncogenic TFs (BARX1, DLX6, ELF3, EN1, ETV1, FOXE1, HOXB7, IRX4, IRX5, and SALL1). The expression levels of IRX5 were positively associated with OS of smoker and inversely associated with OS of non-smoker patients with lung adenocarcinoma. We showed that tobacco carcinogen benzo(a)pyrene (BaP) induced upregulation of IRX5 in lung epithelial cells, and Cyclin D1 was a downstream target of IRX5. Furthermore, silencing of IRX5 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor growth in nude mice. These results indicate that tobacco smoke can modulate TFs to facilitate lung carcinogenesis, and inhibition of IRX5 may have therapeutic potentials in NSCLCs.
['Zhang|Da-Lin|DL|', 'Qu|Li-Wei|LW|', 'Ma|Liang|L|', 'Zhou|Yong-Chun|YC|', 'Wang|Gui-Zhen|GZ|', 'Zhao|Xin-Chun|XC|', 'Zhang|Chen|C|', 'Zhang|Yan-Fei|YF|', 'Wang|Min|M|', 'Zhang|Mei-Ying|MY|', 'Yu|Hong|H|', 'Sun|Bei-Bei|BB|', 'Gao|San-Hui|SH|', 'Cheng|Xin|X|', 'Guo|Ming-Zhou|MZ|', 'Huang|Yun-Chao|YC|', 'Zhou|Guang-Biao|GB|']
D000072283:A549 Cells D000818:Animals D002289:Carcinoma, Non-Small-Cell Lung D002460:Cell Line D045744:Cell Line, Tumor D015972:Gene Expression Regulation, Neoplastic D055106:Genome-Wide Association Study D018398:Homeodomain Proteins D006801:Humans D008175:Lung Neoplasms D016688:Mice, Inbred NOD D016513:Mice, SCID D034622:RNA Interference D000067492:RNAi Therapeutics D014157:Transcription Factors D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
Lung cancer IRX5 Cyclin D1 Tobacco smoke RNAi screening