Overexpression of cyclin D1, due to gene amplification and inactivation of its degradation machinery, (for example, loss of the Fbxo4 E3 ubiquitin ligase or mutations in the cyclin D1 degron), directly contributes to the development and progression of ESCC9–11, supporting a model wherein targeting cyclin D1-CDK4/6 could be effective for ESCC patients. Here, CDK4 is linked to esophageal squamous cell carcinoma.