Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4

IF 16 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2026-09-02 DOI:10.1016/j.molcel.2026.08.007

Chen Chu,Shanshan Zheng,Ning Mitchell,Zheqi Li,Xixi Zhang,Xiaowei Wu,Tian Zhang,Fabin Dang,Wojciech Michowski,Aleksandra Kolodziejczyk,Miranda L. Xu,Krzysztof W. Kotowski,Zhe Yang,Diego Martinez-Alonso,Joao Paulo,Jindan Sheng,Jane A. Kirby,Finn Groezinger,Yubin Zhou,Miao He,Yoshinaga Ito,Anushree C. Gulvady,Michael I. Cole,Pierre Foidart,Jun Nishida,Xiaohan Ning,Samanta Sharma,Jan M. Suski,Anne Fassl,Yu Zhou,Yan Geng,Wenyi Wei,Steven P. Gygi,Kornelia Polyak,Kai W. Wucherpfennig,Piotr Sicinski

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Abstract

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.

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Cyclin E-CDK2通过BRD4调控癌细胞转录程序和免疫治疗反应

周期蛋白e -周期蛋白依赖性激酶2 （CDK2）复合物是哺乳动物细胞周期机制的一个组成部分，驱动细胞分裂。细胞周期蛋白E-CDK2的过度激活在人类癌症中很常见。小分子CDK2抑制剂在癌症患者的临床试验中进行了测试。在这里，我们报道了周期蛋白E-CDK2在调节癌细胞的整体转录程序中具有细胞周期无关的功能。CDK2磷酸化含溴结构域蛋白4 （BRD4）并调节其染色质关联。癌细胞中细胞周期蛋白E的过度表达和由此导致的CDK2的激活改变了癌细胞的转录组，抑制了干扰素刺激基因的表达，并赋予了对免疫治疗的抗性。相反，CDK2抑制具有相反的作用，并增强了免疫检查点阻断的功效。抑制CDK2还会增加树突状细胞（DCs）对肿瘤的浸润，并增强抗原对CD8 T细胞的交叉呈递。这些研究揭示了细胞周期蛋白E-CDK2在肿瘤发生中的额外功能，并确定了临床可用化合物抑制CDK2作为增强免疫检查点阻断的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.