β‐TrCP is a key E3 ubiquitin ligase and plays important roles in multiple human cancers including ESCC, and increases the ubiquitination level and stability of SNAIL which plays an importance role in regulating cancer stemness.[5, 6, 15] In this study, we identified OTUD6B as a potent DUB of β‐TrCP that promotes β‐TrCP protein stability via suppressing its ubiquitination and degradation, and interacts with SNAIL to increase the ubiquitination level and stability of SNAIL by β‐TrCP. Here, OTUD6B is linked to esophageal squamous cell carcinoma.