Here, we demonstrate a novel tumor‐promoting function of CDK4/6 in CRC by phosphorylating and activating deubiquitinating enzyme 3 (DUB3)‐mediated deubiquitination and stabilization of YAP1, suggesting that targeting CDK4/6 might be promising for managing CRC and other malignant cancers with dysregulated YAP1 and DUB3. The gene discussed is CDK4; the disease is neoplasm.