ZDHHC17‐Mediated CDK4 Palmitoylation Drives Cell Cycle Progression and Orchestrates Cancer Immune Surveillance

ABSTRACT Uncontrolled cell cycle progression is a hallmark of cancer, tightly regulated by both intrinsic and extrinsic stimuli. However, the role of fatty acids, in particular palmitic acid, in cell cycle control remains incompletely understood. Here, we observe that inhibition of protein palmitoylation by administrating 2‐bromohexadecanoic acid (2‐BP) or depleting ZDHHC17 , leads to profound cell cycle arrest. Mechanistically, ZDHHC17 palmitoylates CDK4, thereby facilitating its interaction with cyclin D1 (encoded by CCND1), a process depending on TRAF6‐mediated K11‐linked ubiquitination of CDK4. While, blockade of either palmitoylation or ubiquitination markedly reduces CDK4 kinase activity, resulting in cell cycle arrest and suppressed tumor growth. Furthermore, Zdhhc17 ‐depletion displays reduced cell cycle progression and immune response in a high fat diet (HFD)‐feeding mouse model. Clinically, high ZDHHC17 expression is positively correlated with non‐response to anti‐PD‐1 therapies in cancer patients, partially due to CDK4‐mediated repression of PD‐L1. Thereby, we propose a rational combination strategy of employing CDK4 inhibitors with immune checkpoint blockers (ICBs) to overcome ZDHHC17‐driven cancers. In sum, our study uncovers a novel cell cycle control mechanism by ZDHHC17‐mediated palmitoylation and TRAF6‐mediated ubiquitination of CDK4, presenting a potential therapeutic avenue by targeting the ZDHHC17‐TRAF6‐CDK4 axis for cell cycle dysregulated cancers.