Our findings reveal a pivotal role of the cyclin‐dependent kinase 4/6–deubiquitinating enzyme 3 (CDK4/6–DUB3) axis in promoting the stabilization and tumor‐promoting function of Yes‐associated protein 1 (YAP1) and provide the preclinical evidence that CDK4/6 inhibitors might be an appealing therapeutic strategy for the treatment of colorectal cancer with aberrantly upregulated DUB3 and YAP1. This evidence concerns the gene USP17L2 and neoplasm.