Fan Guangjian, Sun Lianhui, Shan Peipei, Zhang Xianying, Huan Jinliang, Zhang Xiaohong, Li Dali, Wang Tingting, Wei Tingting, Zhang Xiaohong, Gu Xiaoyang, Yao Liangfang, Xuan Yang, Hou Zhaoyuan, Cui Yongping, Cao Liu, Li Xiaotao, Zhang Shengping, Wang Chuangui
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xinsongjiang Road, Songjiang District, Shanghai 201620, China.
Nat Commun. 2015 Oct 6;6:8450. doi: 10.1038/ncomms9450.
Centrosome amplification is frequent in cancer, but the underlying mechanisms remain unclear. Here we report that disruption of the Kruppel-like factor 14 (KLF14) gene in mice causes centrosome amplification, aneuploidy and spontaneous tumorigenesis. Molecularly, KLF14 functions as a transcriptional repressor of Plk4, a polo-like kinase whose overexpression induces centrosome overduplication. Transient knockdown of KLF14 is sufficient to induce Plk4-directed centrosome amplification. Clinically, KLF14 transcription is significantly downregulated, whereas Plk4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and Plk4 protein expression in human breast and colon cancers. Moreover, KLF14 depletion promotes AOM/DSS-induced colon tumorigenesis. Our findings reveal that KLF14 reduction serves as a mechanism leading to centrosome amplification and tumorigenesis. On the other hand, forced expression of KLF14 leads to mitotic catastrophe. Collectively, our findings identify KLF14 as a tumour suppressor and highlight its potential as biomarker and therapeutic target for cancer.
中心体扩增在癌症中很常见，但其潜在机制仍不清楚。在此我们报告，小鼠中Kruppel样因子14（KLF14）基因的破坏会导致中心体扩增、非整倍体和自发肿瘤发生。在分子水平上，KLF14作为Plk4的转录抑制因子发挥作用，Plk4是一种polo样激酶，其过表达会诱导中心体过度复制。短暂敲低KLF14足以诱导由Plk4介导的中心体扩增。在临床上，KLF14转录显著下调，而Plk4转录在多种癌症类型中上调，并且在人类乳腺癌和结肠癌中，KLF14与Plk4蛋白表达之间存在负相关。此外，KLF14缺失会促进AOM/DSS诱导的结肠肿瘤发生。我们的研究结果表明，KLF14减少是导致中心体扩增和肿瘤发生的一种机制。另一方面，强制表达KLF14会导致有丝分裂灾难。总体而言，我们的研究结果确定KLF14为一种肿瘤抑制因子，并突出了其作为癌症生物标志物和治疗靶点的潜力。
