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Updated: Jun 11, 2026
Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
Published on: August 25, 2021
Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells
Eric Hervouet1, Lisenn Lalier, Emilie Debien
1Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe labellisée Ligue Nationale Contre le Cancer, Nantes, France.
Abstract:
Global DNA hypomethylation is a hallmark of cancer cells, but its molecular mechanisms have not been elucidated. Here, we show that the disruption of Dnmt1/PCNA/UHRF1 interactions promotes a global DNA hypomethylation in human gliomas. We then demonstrate that the Dnmt1 phosphorylations by Akt and/or PKC abrogate the interactions of Dnmt1 with PCNA and UHRF1 in cellular and acellular studies including mass spectrometric analyses and the use of primary cultured patient-derived glioma. By using methylated DNA immunoprecipitation, methylation and CGH arrays, we show that global DNA hypomethylation is associated with genes hypomethylation, hypomethylation of DNA repeat element and chromosomal instability. Our results reveal that the disruption of Dnmt1/PCNA/UHRF1 interactions acts as an oncogenic event and that one of its signatures (i.e. the low level of mMTase activity) is a molecular biomarker associated with a poor prognosis in GBM patients. We identify the genetic and epigenetic alterations which collectively promote the acquisition of tumor/glioma traits by human astrocytes and glial progenitor cells as that promoting high proliferation and apoptosis evasion.
Insights
Global DNA hypomethylation in cancer is linked to disrupted Dnmt1/PCNA/UHRF1 interactions. This disruption, driven by Dnmt1 phosphorylation, promotes glioma development and serves as a biomarker for poor prognosis in glioblastoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Global DNA hypomethylation is a known hallmark of cancer, but its underlying molecular mechanisms remain unclear.
- Understanding these mechanisms is crucial for identifying new therapeutic targets and biomarkers in cancer, particularly in gliomas.
Purpose of the Study:
- To elucidate the molecular mechanisms driving global DNA hypomethylation in human gliomas.
- To investigate the role of Dnmt1/PCNA/UHRF1 interactions in glioma development.
- To identify potential molecular biomarkers for glioblastoma prognosis.
Main Methods:
- Utilized cellular and acellular studies, including mass spectrometric analyses.
- Employed primary cultured patient-derived glioma samples.
- Applied methylated DNA immunoprecipitation, methylation arrays, and CGH arrays.
Main Results:
- Disruption of Dnmt1/PCNA/UHRF1 interactions promotes global DNA hypomethylation in human gliomas.
- Dnmt1 phosphorylation by Akt and/or PKC abrogates Dnmt1 interactions with PCNA and UHRF1.
- Global DNA hypomethylation correlates with gene hypomethylation, DNA repeat element hypomethylation, and chromosomal instability.
- Low methyltransferase (mMTase) activity is identified as a molecular biomarker associated with poor prognosis in glioblastoma multiforme (GBM) patients.
Conclusions:
- Disruption of Dnmt1/PCNA/UHRF1 interactions is an oncogenic event in glioma development.
- Epigenetic alterations promoting Dnmt1/PCNA/UHRF1 disruption contribute to glioma traits like high proliferation and apoptosis evasion.
- Low mMTase activity serves as a prognostic biomarker for GBM.
