LAUSR

Neuroendocrine carcinoma (NEC) is a highly aggressive subtype of the neuroendocrine tumor with an extremely poor prognosis. We have previously conducted a comprehensive genomic analysis of over 100 cases of NEC of the gastrointestinal system (GIS‐NEC) and unraveled its unique and organ‐specific genomic drivers. However, the epigenomic features of GIS‐NEC remain unexplored. In this study, we have described the epigenomic landscape of GIS‐NEC and small cell lung carcinoma (SCLC) by integrating motif enrichment analysis from the assay of transposase‐accessible chromatin sequencing (ATAC‐seq) and enhancer profiling from a novel cleavage under targets and tagmentation (CUT&Tag) assay for H3K27ac and identified ELF3 as one of the super‐enhancer–related transcriptional factors in NEC. By combining CUT&Tag and knockdown RNA sequencing for ELF3, we uncovered the transcriptional network regulated by ELF3 and defined its distinctive gene signature, including AURKA, CDC25B, CLDN4, ITGB6, and YWAHB. Furthermore, a loss‐of‐function assay revealed that ELF3 depletion led to poor cell viability. Finally, using gene expression of clinical samples, we successfully divided GIS‐NEC patients into two subgroups according to the ELF3 signature and demonstrated that tumor‐promoting pathways were activated in the ELF3 signature–high group. Our findings highlight the transcriptional regulation of ELF3 as an oncogenic transcription factor and its tumor‐promoting properties in NEC.