title: Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target.
abstract: The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To study the transcriptional impact of NKX2-1 amplification, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma and analyzed DNA-binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation. Integration of these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1. Further cistromic and overexpression analyses indicated that NKX2-1 can cooperate with the forkhead box transcription factor FOXA1 to regulate LMO3 gene expression. RNAi analysis of NKX2-1-amplified cells compared with nonamplified cells demonstrated that LMO3 mediates cell survival downstream from NKX2-1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transcriptional signal transducer in NKX2-1-amplified lung adenocarcinomas.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Hideo
authors: H
authors: Watanabe
authors: Joshua M
authors: JM
authors: Francis
authors: Michele S
authors: MS
authors: Woo
authors: Banafsheh
authors: B
authors: Etemad
authors: Wenchu
authors: W
authors: Lin
authors: Daniel F
authors: DF
authors: Fries
authors: Shouyong
authors: S
authors: Peng
authors: Eric L
authors: EL
authors: Snyder
authors: Purushothama Rao
authors: PR
authors: Tata
authors: Francesca
authors: F
authors: Izzo
authors: Anna C
authors: AC
authors: Schinzel
authors: Jeonghee
authors: J
authors: Cho
authors: Peter S
authors: PS
authors: Hammerman
authors: Roel G
authors: RG
authors: Verhaak
authors: William C
authors: WC
authors: Hahn
authors: Jayaraj
authors: J
authors: Rajagopal
authors: Tyler
authors: T
authors: Jacks
authors: Matthew
authors: M
authors: Meyerson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000230:Adenocarcinoma / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D060588:LIM Domain Proteins; C502335:LMO3 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors