1. Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer.
- Author
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Hokari S, Tamura Y, Kaneda A, Katsura A, Morikawa M, Murai F, Ehata S, Tsutsumi S, Ishikawa Y, Aburatani H, Kikuchi T, Miyazono K, and Koinuma D
- Subjects
- Apoptosis genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung mortality, Cell Line, Tumor, Cell Survival genetics, Chromatin Immunoprecipitation Sequencing, Gene Expression Regulation, Neoplastic genetics, Gene Ontology, Genome-Wide Association Study, Humans, Immunohistochemistry, Lung Neoplasms metabolism, Lung Neoplasms mortality, Nucleotide Motifs, Prognosis, Protein Binding, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, RNA Interference, RNA-Seq, Small Cell Lung Carcinoma metabolism, Small Cell Lung Carcinoma mortality, Tissue Array Analysis, Basic Helix-Loop-Helix Transcription Factors metabolism, Carcinoma, Non-Small-Cell Lung genetics, Cell Proliferation genetics, Lung Neoplasms genetics, Small Cell Lung Carcinoma genetics, Thyroid Nuclear Factor 1 metabolism
- Abstract
Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Published
- 2020
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