Disruption of enhancer-driven S100A14 expression promotes esophageal carcinogenesis

Cancer Lett. 2022 Oct 1:545:215833. doi: 10.1016/j.canlet.2022.215833. Epub 2022 Jul 30.

Abstract

Increasing evidence have revealed that epigenomic and genomic factors jointly contribute to the malignancy of esophageal squamous cell carcinoma (ESCC). However, little is known regarding how enhancers regulate tumor suppressors and drive the tumorigenesis of ESCC. Here, we characterized S100A14 as a tumor suppressor in ESCC and showed that S100A14 deficiency dramatically promoted 4-nitroquinoline-1-oxide (4NQO) -induced tumorigenesis of ESCC and shortened survival of mice. Intriguingly, we found that S100A14 expression was driven by enhancer, and disruption of enhancer decreased the S100A14 expression in ESCC. Mechanistic investigation showed that S100A14 deficiency triggered aberrant differentiated program. TP63, SOX2 and EP300 occupied the enhancer region of S100A14 gene locus and regulated the expression of S100A14. Consistently, S100A14 is downregulated in ESCC tissues compared with their corresponding adjacent normal tissues, and lower S100A14 expression predicts poorer overall survival. Collectively, disruption of enhancer-regulated S100A14 induces ESCC tumorigenesis and it acts as a critical driver of ESCC tumorigenesis.

Keywords: ESCC; Enhancer; S100A14; Tumor-suppressor; Tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Squamous Cell* / chemically induced
  • Carcinoma, Squamous Cell* / genetics
  • Carcinoma, Squamous Cell* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Esophageal Neoplasms* / chemically induced
  • Esophageal Neoplasms* / genetics
  • Esophageal Squamous Cell Carcinoma* / genetics
  • Gene Expression Regulation, Neoplastic
  • Mice