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

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 hypermethylated 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 cancerspecific 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.

Long Noncoding RNA RP11-357H14.17 Plays an Oncogene Role in Gastric Cancer by Activating ATF2 Signaling and Enhancing Treg Cells

“…LncRNA significantly regulates gene expression in both nucleus and cytoplasm [ 3 ]. In the nucleus, lncRNA binds to the Polycomb Group protein (PcG) complex to induce histone trimethylation and regulate mRNA expression of related genes at the transcriptional level [ 13 ]. At the same time, lncRNAs directly bind to promoters and regulate gene expression [ 14 ].…”

“…As previously mentioned, lncRNAs, together with miRNAs, act as sponges and induce a “ceRNA” to regulate gene expression [ 3 ]. On the other hand, lncRNA also affects the stability of proteins and inhibits their expression at the posttranscriptional level [ 13 ]. In the present study, by analyzing the TCGA-STAD data, we found that RP11-357H14.17 is the most up-regulated within human gastric cancer.…”

“…the Polycomb Group protein (PcG) complex to induce histone trimethylation and regulate mRNA expression of related genes at the transcriptional level [13]. At the same time, lncRNAs directly bind to promoters and regulate gene expression [14].…”

TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

“…Upregulation of the H3K27me3 methyl-transferase EZH2 has been observed in various cancers. EZH2 is associated with a high proliferation rate, aggressive tumor subtypes, and poor outcome of patients with cancer 14 . In addition, EZH2 is reported to contribute to chemotherapy response, and EZH2 inhibitors have been proven to reverse drug resistance in cancers 2 , 15 .…”

TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

“…Up-regulation of the H3K27me3 methyltransferase EZH2 has been observed in various cancers. EZH2 is associated with a high proliferation rate, aggressive tumor subtypes, and poor outcome of patients with cancer [14]. In addition, EZH2 is reported to contribute to chemotherapy response, and EZH2 inhibitors have been proven to reverse drug-resistance in cancers [2,15].…”