Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target.
Genes Dev, 2013/1/15;27(2):197-210.
Watanabe H[1], Francis JM, Woo MS, Etemad B, Lin W, Fries DF, Peng S, Snyder EL, Tata PR, Izzo F, Schinzel AC, Cho J, Hammerman PS, Verhaak RG, Hahn WC, Rajagopal J, Jacks T, Meyerson M
Affiliations
PMID: 23322301DOI: 10.1101/gad.203208.112
Impact factor: 12.89
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.
MeSH terms
Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenocarcinoma of Lung; Cell Line, Tumor; Chromatin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 3-alpha; Humans; LIM Domain Proteins; Lung Neoplasms; Nuclear Proteins; Protein Binding; Protein Interaction Domains and Motifs; Thyroid Nuclear Factor 1; Transcription Factors
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