Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis

Nat Commun. 2021 Jul 22;12(1):4457. doi: 10.1038/s41467-021-24813-2.


The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Enhancer Elements, Genetic*
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophageal Squamous Cell Carcinoma / genetics*
  • Esophageal Squamous Cell Carcinoma / secondary
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Ontology
  • Histone Code / genetics
  • Humans
  • Lymphatic Metastasis / genetics
  • Male
  • Middle Aged
  • Oncogenes
  • Transcription Factors / genetics


  • Transcription Factors