ΔNp63 is a known master transcription factor in the Basal-like A subtype of pancreatic ductal adenocarcinoma (PDAC). However, ΔNp63-associated biomarkers and therapeutic vulnerabilities have not been defined. Through integration of RNA-sequencing, ChIP-sequencing, ChRO-sequencing, and HiChIP analyses, employing both PDAC patient-derived xenografts (PDX) and a PDAC cell line expressing ΔNp63, Wang and colleagues discovered a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP). Integrated analyses identified novel ΔNp63-dependent super enhancer transcriptional targets, which the authors validated using CRISPR-dCas9-KRAB epigenomic editing. The authors also demonstrated that B-STEP confers higher bromodomain and extra-terminal (BET) protein inhibitor sensitivity, as pan-BET inhibitor JQ1 effectively abrogated ΔNp63-dependent enhancer transcription and slowed PDAC PDX growth. Furthermore, the authors unveiled a positive correlation between the number of chromatin contacts emanating from ΔNp63 enhancers and ΔNp63 enhancer transcription and verified the unique detectability of ΔNp63-derived enhancer RNAs in basal-like A PDAC tissue using RNA in situ hybridization. Altogether, this...

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