In this study, we provided several lines of evidence that ZNF282 functions as an E2F1 co-activator in ESCC cells: ZNF282 interacted with and enhanced the transcriptional activity of E2F1; depletion of ZNF282 caused reduction in the expression of endogenous E2F1 target genes including CCND2, CCNA1, CDC2, and CDC6; ZNF282 was recruited to the promoters of CCNA1 and CDC6 genes, but not to the promoter of E2F1 gene, indicating a direct involvement of ZNF282 in transcriptional control of a subset of E2F1 target genes. This evidence concerns the gene CCND2 and esophageal squamous cell carcinoma.