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

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

  • Cell Death Discov. 2023 Oct 3;9(1):367. doi: 10.1038/s41420-023-01667-9.
Yuchong Peng 1 2 3,  Youhong Liu 4 5,  Rirong Zheng 1 2 3,  Yubing Ye 1 2 3,  Yongming Fu 1 2 3,  Linglong Yin 6,  Yingxue Gao 4 5,  Yuxin Fu 4 5,  Xuli Qi 4 5,  Tanggang Deng 1 2 3,  Songwei Zhang 4 5,  Xiong Li 7 8 9 10
Affiliations

Affiliations

  • 1 Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.
  • 2 Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China.
  • 3 NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China.
  • 4 Department of Oncology, Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 5 Hunan Key Laboratory of Molecular Radiation Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 6 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China.
  • 7 Key Laboratory of Clinical Precision Pharmacy of Guangdong Higher Education Institutes, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China. lixiong@gdpu.edu.cn.
  • 8 Key Specialty of Clinical Pharmacy, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510699, China. lixiong@gdpu.edu.cn.
  • 9 NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China. lixiong@gdpu.edu.cn.
  • 10 School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510006, China. lixiong@gdpu.edu.cn.
PMID: 37788997 DOI: 10.1038/s41420-023-01667-9
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.

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