PLK1通过调节磷酸化依赖性UHRF1蛋白稳定性来维持DNA甲基化和细胞活力。

PLK1 maintains DNA methylation and cell viability by regulating phosphorylation-dependent UHRF1 protein stability.

作者信息

Peng Yuchong, Liu Youhong, Zheng Rirong, Ye Yubing, Fu Yongming, Yin Linglong, Gao Yingxue, Fu Yuxin, Qi Xuli, Deng Tanggang, Zhang Songwei, Li Xiong

机构信息

Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.

Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.

出版信息

Cell Death Discov. 2023 Oct 3;9(1):367. doi: 10.1038/s41420-023-01667-9.

DOI:10.1038/s41420-023-01667-9

PMID:37788997

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10547799/

Abstract

PLK1 is a key serine/threonine kinase as well as a master mitotic regulator, but it has never been reported that PLK1 regulates DNA methylation. In the present study, we for the first time found that PLK1 inhibition disrupted global DNA methylation and elevated the expression level of tumor suppressor genes. Mechanistically, we found that PLK1 interacts UHRF1 protein to induce its phosphorylation at serine 265. Phosphorylation is required for the maintenance of UHRF1 protein stability by recruiting a deubiquitinase USP7. Conversely, PLK1 inhibition decreases UHRF1 protein interaction with USP7 and activates the ubiquitin-proteasome pathway, thereby accelerating UHRF1 protein degradation. UHRF1 degradation decreases the recruitment of DNMT1 to chromatin, and decreases the level of genome-wide DNA methylation, thereby elevating the expression of tumor suppressor genes and decreasing cell viability. We here presented the first report on the novel role of PLK1 in DNA methylation maintenance through UHRF1-DNMT1 pathway, and revealed a novel anticancer mechanism of PLK1 inhibitors.

摘要

PLK1是一种关键的丝氨酸/苏氨酸激酶，也是一种主要的有丝分裂调节因子，但此前从未有报道称PLK1调节DNA甲基化。在本研究中，我们首次发现抑制PLK1会破坏整体DNA甲基化，并提高肿瘤抑制基因的表达水平。从机制上来说，我们发现PLK1与UHRF1蛋白相互作用，诱导其丝氨酸265位点发生磷酸化。通过招募去泛素化酶USP7来维持UHRF1蛋白稳定性需要磷酸化。相反，抑制PLK1会减少UHRF1蛋白与USP7的相互作用，并激活泛素-蛋白酶体途径，从而加速UHRF1蛋白的降解。UHRF1的降解会减少DNMT1募集到染色质上，降低全基因组DNA甲基化水平，从而提高肿瘤抑制基因的表达并降低细胞活力。我们在此首次报道了PLK1通过UHRF1-DNMT1途径在维持DNA甲基化中的新作用，并揭示了PLK1抑制剂的一种新的抗癌机制。