ChIP‐qPCR and EMSA demonstrated that USF2 could bind to the promoter regions of Rad17 and NELFA. Moreover, USF2 knockdown led to the reduced expression of Rad17 and NELFA. Taken together, these results indicate that the molecular mechanism by which USF2 is involved in ESCC onset and progression might partially be explained by the increased expression of Rad17 and NELFA. The gene discussed is NELFA; the disease is esophageal squamous cell carcinoma.