Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma

Nat Commun. 2020 Jul 22;11(1):3675. doi: 10.1038/s41467-020-17227-z.


Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/β-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics*
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation Sequencing
  • Cohort Studies
  • CpG Islands
  • DNA Methylation
  • Datasets as Topic
  • Epigenesis, Genetic*
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophageal Neoplasms / surgery
  • Esophageal Squamous Cell Carcinoma / genetics*
  • Esophageal Squamous Cell Carcinoma / pathology
  • Esophageal Squamous Cell Carcinoma / surgery
  • Esophagectomy
  • Esophagus / pathology
  • Esophagus / surgery
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genomics
  • Heterochromatin / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Male
  • Middle Aged
  • Promoter Regions, Genetic / genetics
  • Proteomics
  • RNA-Seq
  • Whole Genome Sequencing


  • Biomarkers, Tumor
  • Heterochromatin
  • Histones