Disruption of enhancer-driven S100A14 expression promotes esophageal carcinogenesis

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.

Automated summary

Studies have shown that enhancer-regulated S100A14 acts as a tumor suppressor in esophageal squamous cell carcinoma (ESCC). Deficiency in S100A14 promotes tumorigenesis and decreases the survival of mice. S100A14 expression is regulated by enhancers, and disruption of enhancers leads to decreased S100A14 expression. Mechanistic investigation reveals that S100A14 deficiency triggers abnormal differentiation. Downregulation of S100A14 in ESCC tissues is associated with poorer overall survival.