Zhou Kening, He Yingying, Lin Xi, Zhou Huihao, Xu Xiaomin, Xu Jingui
Department of Gynaecology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou City, Zhejiang Province, 324000, China.
Department of Pathology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou City, Zhejiang Province, 324000, China.
Cell Death Discov. 2024 Sep 30;10(1):419. doi: 10.1038/s41420-024-02190-1.
Endometrial cancer (EC), as one of the most common cancers, severely threatens female reproductive health. Our previous study has shown that Kinesin family member C1 (KIFC1) played crucial roles in the progression of EC. In addition, abnormal centrosome amplification, which was reported to be partially regulated by KIFC1, usually occurred in different cancers. However, whether KIFC1 promoted EC through centrosome amplification and the potential mechanism remain to be revealed. The present study demonstrated that overexpressed KIFC1, which exhibited a worse prognosis, had a positive correlation with an increased number of centrosomes in human EC samples. In addition, KIFC1 overexpression in EC cells prompted centrosome amplification, chromosomal instability, and cell cycle progression. Moreover, we demonstrated that KIFC1 inhibited E3 ubiquitin-protein ligase TRIM37 to maintain the stability of PLK4 by reducing its ubiquitination degradation, and finally promoting centrosome amplification and EC progression in vitro. Finally, the contributing role of KIFC1 and the inhibitory effect of TRIM37 on EC development and metastasis was verified in a nude mouse xenograft model. Our study elucidated that KIFC1 depends on TRIM37-mediated reduced ubiquitination degradation of PLK4 to promote centrosome amplification and EC progression, thus providing a potential prognostic marker and promising therapeutic target for EC in the future.
子宫内膜癌（EC）作为最常见的癌症之一，严重威胁女性生殖健康。我们之前的研究表明，驱动蛋白家族成员C1（KIFC1）在EC进展中起关键作用。此外，据报道，异常的中心体扩增通常发生在不同癌症中，且部分受KIFC1调控。然而，KIFC1是否通过中心体扩增促进EC以及潜在机制仍有待揭示。本研究表明，过表达的KIFC1预后较差，在人类EC样本中与中心体数量增加呈正相关。此外，EC细胞中KIFC1的过表达促使中心体扩增、染色体不稳定和细胞周期进程。而且，我们证明KIFC1通过减少E3泛素蛋白连接酶TRIM37对PLK4的泛素化降解来维持PLK4的稳定性，最终在体外促进中心体扩增和EC进展。最后，在裸鼠异种移植模型中验证了KIFC1的促进作用以及TRIM37对EC发展和转移的抑制作用。我们的研究阐明，KIFC1依赖于TRIM37介导的PLK4泛素化降解减少来促进中心体扩增和EC进展，从而为未来的EC提供了一个潜在的预后标志物和有前景的治疗靶点。
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