Molecular cell · 2026
Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4.
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Chu Chen, Zheng Shanshan, Mitchell Ning, Li Zheqi, Zhang Xixi, Wu Xiaowei, Zhang Tian, Dang Fabin, Michowski Wojciech, Kolodziejczyk Aleksandra, Xu Miranda L, Kotowski Krzysztof W, Yang Zhe, Martinez-Alonso Diego, Paulo Joao, Sheng Jindan, Kirby Jane A, Groezinger Finn, Zhou Yubin, He Miao, Ito Yoshinaga, Gulvady Anushree C, Cole Michael I, Foidart Pierre, Nishida Jun, Ning Xiaohan, Sharma Samanta, Suski Jan M, Fassl Anne, Zhou Yu, Geng Yan, Wei Wenyi, Gygi Steven P, Polyak Kornelia, Wucherpfennig Kai W, Sicinski Piotr
Аннотация
The cyclin E-cyclin-dependent kinase 2 (CDK2) complex is a component of mammalian cell-cycle machinery that drives cell division. Hyperactivation of cyclin E-CDK2 is frequent in human cancers. Small-molecule CDK2 inhibitors are tested in clinical trials for cancer patients. Here, we report that cyclin E-CDK2 has a cell-cycle-independent function in regulating the global transcriptional program of cancer cells. CDK2 phosphorylates bromodomain-containing protein-4 (BRD4) and regulates its chromatin association. Overexpression of cyclin E and the resulting activation of CDK2 in cancer cells alter the cancer cell transcriptome, repress the expression of interferon-stimulated genes, and confer resistance to immunotherapy. Conversely, CDK2 inhibition has the opposite effect and augments the efficacy of immune checkpoint blockade. CDK2 inhibition also increases tumor infiltration by dendritic cells (DCs) and enhances antigen cross-presentation to CD8 T cells. These studies reveal an additional function of cyclin E-CDK2 in tumorigenesis and identify inhibition of CDK2 with clinically available compounds as a strategy for enhancing immune checkpoint blockade.
Предметные рубрики MeSH
HumansCyclin ECyclin-Dependent Kinase 2Bromodomain Containing ProteinsCell Cycle ProteinsTranscription FactorsAnimalsCell Line, TumorGene Expression Regulation, NeoplasticTranscription, GeneticDendritic CellsOncogene ProteinsImmunotherapyImmune Checkpoint InhibitorsCD8-Positive T-LymphocytesNeoplasmsMicePhosphorylationNuclear ProteinsProtein Kinase InhibitorsSignal Transduction