Reactivation of super-enhancers by KLF4 in human Head and Neck Squamous Cell Carcinoma

Oncogene. 2020 Jan;39(2):262-277. doi: 10.1038/s41388-019-0990-4. Epub 2019 Sep 2.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a disease of significant morbidity and mortality and rarely diagnosed in early stages. Despite extensive genetic and genomic characterization, targeted therapeutics and diagnostic markers of HNSCC are lacking due to the inherent heterogeneity and complexity of the disease. Herein, we have generated the global histone mark based epigenomic and transcriptomic cartogram of SCC25, a representative cell type of mesenchymal HNSCC and its normal oral keratinocyte counterpart. Examination of genomic regions marked by differential chromatin states and associated with misregulated gene expression led us to identify SCC25 enriched regulatory sequences and transcription factors (TF) motifs. These findings were further strengthened by ATAC-seq based open chromatin and TF footprint analysis which unearthed Krüppel-like Factor 4 (KLF4) as a potential key regulator of the SCC25 cistrome. We reaffirm the results obtained from in silico and chromatin studies in SCC25 by ChIP-seq of KLF4 and identify ΔNp63 as a co-oncogenic driver of the cancer-specific gene expression milieu. Taken together, our results lead us to propose a model where elevated KLF4 levels sustains the oncogenic state of HNSCC by reactivating repressed chromatin domains at key downstream genes, often by targeting super-enhancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromatin / genetics
  • Enhancer Elements, Genetic*
  • Epigenomics
  • Gene Expression Regulation, Neoplastic
  • Histone Code / genetics
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Regulatory Sequences, Nucleic Acid
  • Squamous Cell Carcinoma of Head and Neck / genetics*
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Transcription Factors / genetics
  • Transcriptome / genetics*

Substances

  • Chromatin
  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Transcription Factors