Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Genes Dev. 2013 Jan 15;27(2):197-210. doi: 10.1101/gad.203208.112.
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.
NKX2-1 转录因子是正常肺发育的调节因子，也是人类肺腺癌中扩增最显著的基因。为了研究 NKX2-1 扩增的转录影响，我们在人类肺腺癌中生成了与 NKX2-1 扩增相关的表达特征，并通过全基因组染色质免疫沉淀分析了 NKX2-1 的 DNA 结合位点。这些表达和染色质分析的整合确定了 LMO3（自身编码转录调节剂）是 NKX2-1 的候选直接转录靶标。进一步的染色质和过表达分析表明，NKX2-1 可以与叉头框转录因子 FOXA1 合作调节 LMO3 基因的表达。与非扩增细胞相比，对 NKX2-1 扩增细胞进行 RNAi 分析表明，LMO3 介导 NKX2-1 下游的细胞存活。我们的研究结果为 NKX2-1 的转录调控网络提供了新的见解，并表明 LMO3 是 NKX2-1 扩增肺腺癌中的转录信号转导因子。
