Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells.
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.
Hervouet
Eric
E
Centre de Recherche en Cancérologie Nantes-Angers, INSERM, U892, Equipe labellisée Ligue Nationale Contre le Cancer, Nantes, France.
Lalier
Lisenn
L
Debien
Emilie
E
Cheray
Mathilde
M
Geairon
Audrey
A
Rogniaux
Hélène
H
Loussouarn
Delphine
D
Martin
Stéphane A
SA
Vallette
François M
FM
Cartron
Pierre-François
PF
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D009457:Neuroglia / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D022762:CCAAT-Enhancer-Binding Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C