Negative regulation of DNMT3A de novo DNA methylation by frequently overexpressed UHRF family proteins as a mechanism for widespread DNA hypomethylation in cancer
| Autor: | Wenqiang Yu, Fei Li, Junying Zhang, Taiping Chen, Hongbin Ji, Haijun Zhu, Liangliang Xu, Jiwen Li, Qihan Wu, Yuanhui Jia, Lan Fang, Jialun Li, James X. Du, Jiemin Wong, Yan Li, Pishun Li, Jackie J.D. Han, Yan Feng, Ruiping Wang, Hao Cheng |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Biology Biochemistry Article 03 medical and health sciences chemistry.chemical_compound DNA Maintenance Genetics medicine cancer Epigenetics UHRF1 Molecular Biology UHRF2 DNMT1 Cancer DNA Cell Biology Methylation medicine.disease Molecular biology 030104 developmental biology chemistry embryonic structures DNA methylation Cancer research DNMT3A hypomethylation DNA hypomethylation |
| Zdroj: | Cell Discovery |
| ISSN: | 2056-5968 |
| DOI: | 10.1038/celldisc.2016.7 |
| Popis: | Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation. Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth. We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A. |
| Databáze: | OpenAIRE |
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