Targeting CDK4/6 suppresses colorectal cancer by destabilizing YAP1

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Colorectal cancer (CRC) is a leading cause of cancer-related death globally.
• Yes-associated protein 1 (YAP1) dysregulation promotes cancer stemness and chemoresistance in CRC.
• Direct YAP1 targeting strategies are limited by a lack of binding pockets and toxicity.

Purpose of the Study:

• To identify Food and Drug Administration (FDA)-approved drugs that can target YAP1 in colorectal cancer.
• To elucidate the molecular mechanism by which YAP1 is regulated in CRC.
• To explore potential therapeutic strategies for CRC targeting the identified pathway.

Main Methods:

• Screening of FDA-approved drugs for YAP1-targeting activity in CRC cells and patient-derived xenograft models.
• Identification of deubiquitinating enzyme 3 (DUB3) as a YAP1 deubiquitinase using biochemical assays.
• Investigation of the role of cyclin-dependent kinase 4/6 (CDK4/6) in regulating DUB3 and YAP1 phosphorylation and stability.
• Histological analysis of DUB3 and YAP1 expression in CRC specimens.

Main Results:

• Abemaciclib, a CDK4/6 inhibitor, induces proteasome-dependent degradation of YAP1, inhibiting CRC progression.
• DUB3 was identified as the deubiquitinase responsible for YAP1 stabilization in CRC.
• CDK4/6 directly phosphorylates DUB3 at Ser41, activating its deubiquitinase activity towards YAP1.
• Inhibition of CDK4/6 or mutation of Ser41 in DUB3 leads to YAP1 degradation and suppressed tumor progression.
• A positive correlation between DUB3 and YAP1 expression was observed in CRC specimens.

Conclusions:

• The CDK4/6-DUB3 pathway promotes YAP1 stabilization and oncogenic function in colorectal cancer.
• Targeting CDK4/6 represents a promising therapeutic strategy for CRC patients with elevated DUB3 and YAP1.
• This study uncovers a novel mechanism of YAP1 regulation and provides a potential therapeutic avenue for CRC.