CDK4/6-mediated phosphorylation of DUB3 promotes YAP1 stability and hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, frequently characterized by high expression and activation of Yes-associated protein 1 (YAP1), a key effector in the Hippo signaling pathway. Despite its crucial role in HCC progression, effective therapies directly targeting YAP1 remain challenging, underscoring the need to explore the regulatory mechanisms underlying its aberrant expression and activation. In this study, we identify cyclin-dependent kinase 4 and 6 (CDK4/6) as uncharacterized regulators of YAP1 in HCC. Genetic ablation or pharmacological inhibition of CDK4/6 significantly destabilizes YAP1 and attenuates its oncogenic functions both in vitro and in vivo. Furthermore, we establish DUB3 as a bona fide deubiquitinase of YAP1. Mechanistically, CDK4/6 directly phosphorylates DUB3, enhancing its deubiquitinase activity towards YAP1, which promotes tumor growth and contributes to chemo-resistance in HCC. Collectively, our findings unveil the previously unrecognized function and significance of the CDK4/6-DUB3 axis in stabilizing YAP1 and provide a rationale for potential therapeutic interventions in the treatment of HCC.