ATF4 and cancer: In human esophageal squamous cell carcinoma, the levels of NEDD8, NAE1, UBA3, and UBE2M are increased significantly, which is positively correlated with high-grade malignancy and postoperative recurrence as well as worse overall survival of patients.336,337 The hyperactivated neddylation pathway activates CRL/SCFβTrCP E3 to destabilize the activating transcription factor 4 (ATF4), thus protecting cells from apoptosis by inhibiting the extrinsic apoptosis mediated by the ATF4–CHOP–DR5 axis, leading to cancer cell survival.337