In ESCC, UBC12-involved neddylation of CUL1, CUL2, CUL3, CUL4A, and CUL4B activates CRLs, leading to the depletion of activating transcription factor 4 (ATF4) and transrepression of death receptor 5 (DR5), which inhibits extrinsic apoptosis. This evidence concerns the gene ATF4 and esophageal squamous cell carcinoma.