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Open Access Highly Accessed Research article

A systematic approach identifies FOXA1 as a key factor in the loss of epithelial traits during the epithelial-to-mesenchymal transition in lung cancer

Haiyun Wang123*, Clifford A Meyer2, Teng Fei24, Gang Wang5, Fan Zhang5* and X Shirley Liu2

Author Affiliations

1 School of Life Science and Technology, Tongji University, Shanghai 200092, China

2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA

3 Tongji University Advanced Institute of Translational Medicine, Tongji University, Shanghai 200092, China

4 Department of Medical Oncology, Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA

5 Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China

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BMC Genomics 2013, 14:680  doi:10.1186/1471-2164-14-680

Published: 4 October 2013

Abstract

Background

The epithelial-to-mesenchymal transition is an important mechanism in cancer metastasis. Although transcription factors including SNAIL, SLUG, and TWIST1 regulate the epithelial-to-mesenchymal transition, other unknown transcription factors could also be involved. Identification of the full complement of transcription factors is essential for a more complete understanding of gene regulation in this process. Chromatin immunoprecipitation-sequencing (ChIP-Seq) technologies have been used to detect genome-wide binding of transcription factors; here, we developed a systematic approach to integrate existing ChIP-Seq and transcriptome data. We scanned multiple transcription factors to investigate their functional impact on the epithelial-to-mesenchymal transition in the human A549 lung adenocarcinoma cell line.

Results

Among the transcription factors tested, impact scores identified the forkhead box protein A1 (FOXA1) as the most significant transcription factor in the epithelial-to-mesenchymal transition. FOXA1 physically associates with the promoters of its predicted target genes. Several critical epithelial-to-mesenchymal transition effectors involved in cellular adhesion and cellular communication were identified in the regulatory network of FOXA1, including FOXA2, FGA, FGB, FGG, and FGL1. The implication of FOXA1 in the epithelial-to-mesenchymal transition via its regulatory network indicates that FOXA1 may play an important role in the initiation of lung cancer metastasis.

Conclusions

We identified FOXA1 as a potentially important transcription factor and negative regulator in the initial stages of lung cancer metastasis. FOXA1 may modulate the epithelial-to-mesenchymal transition via its transcriptional regulatory network. Further, this study demonstrates how ChIP-Seq and expression data could be integrated to delineate the impact of transcription factors on a specific biological process.

Keywords:
The epithelial-to-mesenchymal transition; Lung cancer; ChIP-Seq; FOXA1