Loss of KLF14 triggers centrosome amplification and tumorigenesis.
Loss of KLF14 triggers centrosome amplification and tumorigenesis.
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KLF14 缺失会触发中心体扩增和肿瘤发生
DOI：
10.1038/ncomms9450
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发表时间：
2015-10-06
影响因子：
16.6
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Fan G;Sun L;Shan P;Zhang X;Huan J;Zhang X;Li D;Wang T;Wei T;Zhang X;Gu X;Yao L;Xuan Y;Hou Z;Cui Y;Cao L;Li X;Zhang S;Wang C
中心体扩增在癌症中很常见，但其潜在机制仍不清楚。在这里，我们报告的Kruppel样因子14（KLF 14）基因在小鼠中的破坏导致中心体扩增，非整倍体和自发性肿瘤发生。分子上，KLF 14作为Plk 4的转录抑制因子发挥作用，Plk 4是一种polo样激酶，其过表达诱导中心体过度复制。瞬时敲低KLF 14足以诱导Plk 4指导的中心体扩增。临床上，KLF 14转录显著下调，而Plk 4转录在多种类型的癌症中上调，并且在人乳腺癌和结肠癌中KLF 14和Plk 4蛋白表达之间存在负相关。此外，KLF 14缺失促进AOM/DSS诱导的结肠肿瘤发生。我们的研究结果表明，KLF 14减少作为一种机制，导致中心体扩增和肿瘤发生。另一方面，KLF 14的强制表达导致有丝分裂灾难。总的来说，我们的研究结果将KLF 14确定为肿瘤抑制因子，并突出了其作为癌症生物标志物和治疗靶点的潜力。
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.