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Published on: May 14, 2016
ZDHHC17-Mediated CDK4 Palmitoylation Drives Cell Cycle Progression and Orchestrates Cancer Immune Surveillance
Zekang Wang1, Peipei Song2, Xueji Wu2
1Center of Thoracic Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Summary
ZDHHC17 palmitoylation of CDK4 regulates cell cycle progression. Inhibiting this process halts cancer growth and improves immune response, offering new therapeutic strategies for ZDHHC17-driven cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Uncontrolled cell cycle progression drives cancer.
- The role of fatty acids, like palmitic acid, in cell cycle control is not fully understood.
Purpose of the Study:
- Investigate the role of protein palmitoylation in cell cycle regulation.
- Elucidate the mechanism by which ZDHHC17 influences cell cycle control and cancer progression.
Main Methods:
- Inhibition of protein palmitoylation using 2-bromohexadecanoic acid (2-BP) or ZDHHC17 depletion.
- Analysis of CDK4 interaction with cyclin D1 and its ubiquitination.
- Assessment of CDK4 kinase activity.
- In vivo studies using a high-fat diet (HFD) mouse model.
- Clinical correlation analysis of ZDHHC17 expression and anti-PD-1 therapy response.
Main Results:
- Inhibition of palmitoylation or ZDHHC17 depletion caused cell cycle arrest.
- ZDHHC17 facilitates CDK4-cyclin D1 interaction via TRAF6-mediated ubiquitination, reducing CDK4 kinase activity.
- ZDHHC17 depletion reduced cell cycle progression and immune response in HFD mice.
- High ZDHHC17 expression correlated with non-response to anti-PD-1 therapies due to CDK4-mediated PD-L1 repression.
Conclusions:
- ZDHHC17-mediated palmitoylation and TRAF6-mediated ubiquitination of CDK4 represent a novel cell cycle control mechanism.
- Targeting the ZDHHC17-TRAF6-CDK4 axis offers a therapeutic strategy for cancers with cell cycle dysregulation.
- Combining CDK4 inhibitors with immune checkpoint blockers (ICBs) may overcome ZDHHC17-driven cancer resistance.
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