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

Mol Oncol. 2020 Feb;14(2):277-293. doi: 10.1002/1878-0261.12608. Epub 2019 Dec 15.


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.

Keywords: ASCL1; ChIP-seq; NKX2-1; SCLC; TTF-1; lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • Cell Survival / genetics
  • Chromatin Immunoprecipitation Sequencing
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Ontology
  • Genome-Wide Association Study
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / genetics*
  • 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 / genetics*
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / mortality
  • Thyroid Nuclear Factor 1 / metabolism*
  • Tissue Array Analysis


  • ASCL1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • NKX2-1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Thyroid Nuclear Factor 1