Profiling of histone modifications reveal tumor microenvironment-acquired super-enhancer regulates progression of esophageal squamous cell carcinoma

In particular, H3K27ac is aberrantly expressed in tumor tissue and stroma and its high expression is significantly correlated with poor prognosis of ESCC patients. We analyzed the H3K27ac ChIP-seq data for primary ESCC tumor tissues and ESCC cell lines and identified hundreds of altered putative super-enhancers (SEs) in ESCC tissues respectively relative to ESCC cell lines. Moreover, these differential SEs contribute to the transcriptomic aberrations in ESCC tissues.

Genes regulated by ESCC tissue- gained SEs are highly expressed in ESCC tissues compared to ESCCthan in cell lines and are mostly enriched in microenvironment-related pathways. We definerefer to these SEs as tumor microenvironment-acquired super-enhancers (TMEA-SEs). Through integrative analysis of ChIP-seq, RNA-seq, scRNA-seq and ATAC-seq data, we identified a TMEA-SE activated in cancer-associated fibroblasts (CAFs) and found that IL1R1 is directly regulated by this TMEA-SE.

We demonstrated that IL1R1 activation can affect CAFs to promotes ESCC cells migration and invasion via CAFs. Collectively, our findings these observations reveal that a critical oncogenic mechanism in ESCC whereby TMEA-SE drive malignancy by activating IL1R1 in CAFs.