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.

PLK1是一种关键的丝氨酸/苏氨酸激酶，也是有丝分裂的主要调节因子，但从未有关于PLK1调节DNA甲基化的报道。在本研究中，我们首次发现PLK1抑制破坏了整体DNA甲基化并提高了抑癌基因的表达水平。从机制上讲，我们发现 PLK1 与 UHRF1 蛋白相互作用，诱导其在丝氨酸 265 处磷酸化。磷酸化是通过招募去泛素酶 USP7 来维持 UHRF1 蛋白稳定性所必需的。相反，PLK1 抑制会减少 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 蛋白降解。UHRF1 降解会减少 DNMT1 向染色质的募集，并降低全基因组 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 通路在 DNA 甲基化维持中的新作用，并揭示了 PLK1 抑制剂的新抗癌机制。