Author:
Watanabe Hideo,Francis Joshua M.,Woo Michele S.,Etemad Banafsheh,Lin Wenchu,Fries Daniel F.,Peng Shouyong,Snyder Eric L.,Tata Purushothama Rao,Izzo Francesca,Schinzel Anna C.,Cho Jeonghee,Hammerman Peter S.,Verhaak Roel G.,Hahn William C.,Rajagopal Jayaraj,Jacks Tyler,Meyerson Matthew
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.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics