FOXM1, a super enhancer-associated gene, is related to poorer prognosis and gemcitabine resistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid tumor; however, the barrier of chemoresistance has yet to be overcome for longer survival. Aberrant gene expression due to epigenetic modification plays an important role in tumorigenesis and treatment. Super enhancers are epigenetic elements that promote targeted gene transcription and ultimately lead to chemoresistance. This study found that the expression of FOXM1 was higher in PDAC tissues and negatively correlated with prognosis. Through RNA sequencing and chromatin immunoprecipitation-sequencing analyses, FOXM1 was found to be regulated by a BRD4-associated super enhancer, which finally promoted gemcitabine resistance via TGFβ/Smad signaling pathway activation. Both TGFβ/Smad-specific inhibitor LY364947 and the BRD4 inhibitor JQ1 decreased the IC50 value of gemcitabine in vitro. Furthermore, combined gemcitabine and JQ1 therapy could not only enhance the therapeutic effect of gemcitabine but also reverse drug resistance in vivo. In conclusion, the super enhancer-associated gene FOMX1 contributes to gemcitabine resistance and is a promising target in PDAC treatment.