Targeting CDK4/6 suppresses colorectal cancer by destabilizing YAP1

Colorectal cancer (CRC) is among the most prevalent and deadly cancers worldwide. The Yes-associated protein 1 (YAP1) is frequently dysregulated in cancers, contributing to cancer stemness, chemoresistance, and cancer-related death. However, strategies directly targeting YAP1 have not yet been successful because of the lack of active binding pockets and unregulated toxicity. In this study, our Food and Drug Administration (FDA)-approved drug screening reveals that abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, dramatically promotes the proteasome-dependent degradation of YAP1, thereby inhibiting tumor progression in CRC cells and patient-derived xenograft models. We further identify deubiquitinating enzyme 3 (DUB3) as the bona fide deubiquitinase of YAP1 in CRC. Mechanistically, CDK4/6 directly phosphorylates DUB3 at Ser41, activating DUB3 to deubiquitinate and stabilize YAP1. Conversely, loss of Ser41 phosphorylation by CDK4/6 inhibition or Ser41A mutation, promotes YAP1 degradation and suppresses YAP1-driven tumor progression. Histological analysis shows a positive correlation between DUB3 and YAP1 expression in CRC specimens. Collectively, our study uncovers a novel oncogenic role of the CDK4/6-DUB3 pathway, which promotes YAP1 stabilization and tumor-promoting function, highlighting that targeting CDK4/6 offers a potential therapeutic strategy for CRC with aberrantly upregulated DUB3 and YAP1.