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Mol Oncol. 2019 Nov 29. doi: 10.1002/1878-0261.12608. [Epub ahead of print]

Comparative analysis of TTF-1-binding DNA regions in small cell lung cancer and non-small cell lung cancer.

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Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, 153-8904, Japan.
Divison of Pathology, the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.


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 co-expressed 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 anti-apoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and anti-apoptotic gene expression by partly coordinating with ASCL1.


ASCL1; ChIP-seq; NKX2-1; SCLC; TTF-1; lung cancer

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