ChIP-Seq

Genetic drivers of malignancies have been widely discovered by genomic sequencing, while the role of regulatory enhancer elements and their aberrations associated with carcinogenesis and metastasis remains unclear for esophageal squamous cell carcinoma (ESCC). Here we surveyed the epigenomic and transcriptomic landscapes of primary esophageal cancers (ECs) and metastatic lymph node cancers (LNCs), analyzing 28 active enhancer marker H3K27ac profiles and 50 transcriptomes in primary ECs, LNCs, and adjacent nonmalignant esophageal tissues (Nor). We identified thousands of gained or lost enhancers and hundreds of altered putative super-enhancers (SEs) respectively relative to adjacent normal esophageal tissues. Intriguingly, ECs and LNCs displayed 1,974 common gained enhancer and 2,715 common lost enhancers, as well as hundreds of group-specific gained or lost enhancers. The alterations of enhancer elements contribute to the transcriptomic aberrations in ECs and LNCs, and dozens of enhancer-linked hallmarks were identified for three groups. Therefore, we propose that these reproducible alterations at regulatory enhancers may drive a set of transcriptomic reprogramming to promote esophageal carcinogenesis. Moreover, common-gained SE-associated genes predisposed a bad clinical prognosis. Gained enhancers and SEs revealed putative driver onco-transcription factors and druggable targets; inhibition of transcription factors which potentially promote the gain of oncogenic enhancers diminished cell proliferation and migration, and administration of small molecule inhibitors to suppress active SEs-predicted targets discovered HSP90AA1 and PDE4B as potential novel ESCC therapeutic targets in ESCC cells and xenograft tumors. Our epigenomic profiling reveals a compendium of somatically reprogrammed cis-regulatory enhancers and SEs during ESCC tumorigenesis and metastasis to lymph nodes, provides a non-genetic pathway for uncovering novel targetable and druggable candidates for cancer treatment using known drugs.