1. ¹Centre of Biotechnology, University of Urbino, Fano, Italy
2. ²Department of Experimental Oncology, European Institute of Oncology, Milan, Italy
3. ³Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
4. ⁴Department of Experimental Medicine and Pathology, University of Rome 'La Sapienza' and INM Neuromed, Pozzilli (IS), Rome, Italy

Correspondence: Dr M Fanelli, Molecular Pathology Lab, Centre of Biotechnology, University of Urbino 'Carlo Bo', Via Campanella 1, Fano (PU) 61032, Italy. E-mail: mirco.fanelli@uniurb.it

Received 5 October 2006; Revised 3 May 2007; Accepted 1 June 2007; Published online 23 July 2007.

Abstract

Cancer is generally characterized by loss of CG dinucleotides methylation resulting in a global hypomethylation and the consequent genomic instability. The major contribution to the general decreased methylation levels seems to be due to demethylation of heterochromatin repetitive DNA sequences. In human immunodeficiency, centromeric instability and facial anomalies syndrome, demethylation of pericentromeric satellite 2 DNA sequences has been correlated to functional mutations of the de novo DNA methyltransferase 3b (DNMT3b), but the mechanism responsible for the hypomethylated status in tumors is poorly known. Here, we report that human glioblastoma is affected by strong hypomethylation of satellite 2 pericentromeric sequences that involves the stem cell compartment. Concomitantly with the integrity of the DNMTs coding sequences, we report aberrations in DNA methyltrasferases expression showing upregulation of the DNA methyltransferase 1 (DNMT1) and downregulation of the de novo DNA methyltransferase 3a (DNMT3a). Moreover, we show that DNMT3a is the major de novo methyltransferase expressed in normal neural progenitor cells (NPCs) and its forced re-expression is sufficient to partially recover the methylation levels of satellite 2 repeats in glioblastoma cell lines. Thus, we speculate that DNMT3a decreased expression may be involved in the early post-natal inheritance of an epigenetically altered NPC population that could be responsible for glioblastoma development later in adult life.