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

  • Author(s): Cao, Wei
  • Lee, Hayan
  • Wu, Wei
  • Zaman, Aubhishek
  • McCorkle, Sean
  • Yan, Ming
  • Chen, Justin
  • Xing, Qinghe
  • Sinnott-Armstrong, Nasa
  • Xu, Hongen
  • Sailani, M Reza
  • Tang, Wenxue
  • Cui, Yuanbo
  • Liu, Jia
  • Guan, Hongyan
  • Lv, Pengju
  • Sun, Xiaoyan
  • Sun, Lei
  • Han, Pengli
  • Lou, Yanan
  • Chang, Jing
  • Wang, Jinwu
  • Gao, Yuchi
  • Guo, Jiancheng
  • Schenk, Gundolf
  • Shain, Alan Hunter
  • Biddle, Fred G
  • Collisson, Eric
  • Snyder, Michael
  • Bivona, Trever G
  • et al.
Abstract

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.

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