Comparative analysis of TTF‐1 binding DNA regions in small‐cell lung cancer and non‐small‐cell lung cancer. Issue 2 (15th December 2019)

• Record Type: Journal Article
• Authors: Hokari, Satoshi; Tamura, Yusuke; Kaneda, Atsushi; Katsura, Akihiro; Morikawa, Masato; Murai, Fumihiko; Ehata, Shogo; Tsutsumi, Shuichi; Ishikawa, Yuichi; Aburatani, Hiroyuki; Kikuchi, Toshiaki; Miyazono, Kohei; Koinuma, Daizo
• Is Part Of: Molecular oncology. Volume 14:Issue 2(2020)
• Page Start: 277
• Page End: 293
• Publication Date: 2019-12-15
• Subjects: ASCL1 -- ChIP‐seq -- lung cancer -- NKX2‐1 -- SCLC -- TTF‐1; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12608
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : A remarkable difference in the thyroid transcription factor‐1 (TTF‐1) binding regions on the genome was identified between lung adenocarcinoma (LDAC) and small‐cell lung carcinoma (SCLC). TTF‐1 inhibits epithelial‐mesenchymal transition in LADC cells, while TTF‐1 cooperates with ASCL1 to induce neuroendocrine differentiation and antiapoptotic function in SCLC cells.