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.