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.
Highlights
Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is a homeodomain-containing master transcription factor (TF) of lung morphogenesis and differentiation of pulmonary epithelial cells (Kimura et al, 1996; Minoo et al, 1999)
thyroid transcription factor-1 (TTF-1) is highly expressed in a subset of small-cell lung carcinoma (SCLC) in association with poor prognosis
Investigation of microarray data from the Cancer Cell Line Encyclopedia (CCLE) (Barretina et al, 2012) showed that the median values of NKX2-1 expression in lung cancers were higher among cancers originating from different tissues (Fig. 1A), and SCLC showed significantly higher expression than other types of lung cancers (Fig. 1B)
Summary
Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is a homeodomain-containing master transcription factor (TF) of lung morphogenesis and differentiation of pulmonary epithelial cells (Kimura et al, 1996; Minoo et al, 1999). TTF-1 is expressed in 75–80% of lung adenocarcinoma (LADC), a nonsmall-cell lung cancer (NSCLC) subtype, and is a marker of the terminal respiratory unit (TRU) subtype (Yatabe et al, 2002). Abbreviations ASCL1, achaete-scute homolog 1; CCLE, cancer cell line encyclopedia; ChIP-seq, chromatin immunoprecipitation-sequencing; EMT, epithelial–mesenchymal transition; GO, gene ontology; IB, immunoblotting; IHC, immunohistochemistry; IP, immunoprecipitation; LADC, lung adenocarcinoma; NSCLC, non-small-cell lung cancer; PLA, proximity ligation assay; qRT-PCR, quantitative real-time reverse transcription–PCR; RNA-seq, RNA-sequencing; SCLC, small-cell lung cancer; TF, transcription factor; TGF-b, transforming growth factor-b; TRU, terminal respiratory unit; TTF-1, thyroid transcription factor-1.
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