Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma

Cancer Res. 2019 Dec 15;79(24):6084-6100. doi: 10.1158/0008-5472.CAN-19-2132. Epub 2019 Sep 24.


Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed "neural" subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the "neural" LUSC. Forced expression of p63 downregulated Brn2 in the "neural" LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted. SIGNIFICANCE: Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/24/6084/F1.large.jpg.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation Sequencing
  • Enhancer Elements, Genetic / genetics
  • Epigenomics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genetic Heterogeneity
  • HEK293 Cells
  • Homeodomain Proteins / metabolism*
  • Humans
  • Lung / pathology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • MicroRNAs
  • POU Domain Factors / metabolism*
  • Primary Cell Culture
  • RNA-Seq
  • SOXB1 Transcription Factors / metabolism*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • Homeodomain Proteins
  • MicroRNAs
  • POU Domain Factors
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • transcription factor Brn-2