School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, UK.
Pharmacol Ther. 2018 Jun;186:138-151. doi: 10.1016/j.pharmthera.2018.01.008. Epub 2018 Mar 1.
Cyclin-dependent kinase 20 (CDK20), or more commonly referred to as cell cycle-related kinase (CCRK), is the latest member of CDK family with strong linkage to human cancers. Accumulating studies have reported the consistent overexpression of CCRK in cancers arising from brain, colon, liver, lung and ovary. Such aberrant up-regulation of CCRK is clinically significant as it correlates with tumor staging, shorter patient survival and poor prognosis. Intriguingly, the signalling molecules perturbed by CCRK are divergent and cancer-specific, including the cell cycle regulators CDK2, cyclin D1, cyclin E and RB in glioblastoma, ovarian carcinoma and colorectal cancer, and KEAP1-NRF2 cytoprotective pathway in lung cancer. In hepatocellular carcinoma (HCC), CCRK mediates virus-host interaction to promote hepatitis B virus-associated tumorigenesis. Further mechanistic analyses reveal that CCRK orchestrates a self-reinforcing circuitry comprising of AR, GSK3β, β-catenin, AKT, EZH2, and NF-κB signalling for transcriptional and epigenetic regulation of oncogenes and tumor suppressor genes. Notably, EZH2 and NF-κB in this circuit have been recently shown to induce IL-6 production to facilitate tumor immune evasion. Concordantly, in a hepatoma preclinical model, ablation of Ccrk disrupts the immunosuppressive tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade via potentiation of anti-tumor T cell responses. In this review, we summarized the multifaceted tumor-intrinsic and -extrinsic functions of CCRK, which represents a novel signalling hub exploitable in cancer immunotherapy.
细胞周期相关激酶（CCRK）又称周期蛋白依赖性激酶 20（CDK20），是 CDK 家族的最新成员，与人类癌症密切相关。越来越多的研究报告称，CCRK 在脑癌、结肠癌、肝癌、肺癌和卵巢癌中持续过表达。这种 CCRK 的异常上调具有临床意义，因为它与肿瘤分期、患者生存时间缩短和预后不良相关。有趣的是，CCRK 扰乱的信号分子是多样化的且具有癌症特异性，包括神经胶质瘤、卵巢癌和结直肠癌中的细胞周期调节剂 CDK2、周期蛋白 D1、周期蛋白 E 和 RB，以及肺癌中的 KEAP1-NRF2 细胞保护途径。在肝细胞癌（HCC）中，CCRK 介导病毒-宿主相互作用以促进乙型肝炎病毒相关肿瘤发生。进一步的机制分析表明，CCRK 协调了一个自我强化的电路，包括 AR、GSK3β、β-catenin、AKT、EZH2 和 NF-κB 信号通路，用于转录和表观遗传调控癌基因和肿瘤抑制基因。值得注意的是，该电路中的 EZH2 和 NF-κB 最近被证明可诱导 IL-6 的产生，以促进肿瘤免疫逃逸。一致地，在肝癌临床前模型中，Ccrk 的缺失破坏了免疫抑制性肿瘤微环境，并通过增强抗肿瘤 T 细胞反应来增强免疫检查点阻断的治疗效果。在这篇综述中，我们总结了 CCRK 的多方面肿瘤内在和外在功能，它代表了一种可用于癌症免疫治疗的新型信号枢纽。
