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.
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References
Aoki A, Suetake I, Miyagawa J, Fujio T, Chijiwa T, Sasaki H et al. (2001). Enzimatic properties of de novo-type mouse DNA (cytosine-5) methyltransferases. Nucleic Acids Res 29: 3506–3512.
Baeza N, Weller M, Yonekawa Y, Kleihues P, Ohgaki H . (2003). PTEN methylation and expression in glioblastomas. Acta Neuropathol (Berlin) 106: 479–485.
Behin A, Hoang-Xuan K, Carpentier AF, Delattre JY . (2003). Primary brain tumours in adults. Lancet 361: 323–331.
Bestor TH . (2000). The DNA methyltransferases of mammals. Hum Mol Genet 9: 2395–2402.
Blanc JL, Wager M, Guilhot J, Kusy S, Bataille B, Chantereau T et al. (2004). Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas. J Neurooncol 68: 275–283.
Calogero A, Lombari V, De Gregorio G, Porcellini A, Ucci S, Arcella A et al. (2004). Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma. Cancer Cell Int 4: 1–12.
Caprodossi S, Pedinotti M, Amantini C, Santoni G, Minucci S, Pelicci PG et al. (2005). Differentiation response of acute promyelocytic leukemia cells and PML/RARα leukemogenic activity studies by Real-time RT–PCR. Mol Biotechnol 30: 231–238.
Chen T, Ueda Y, Dodge JE, Wang Z, Li E . (2003). Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23: 5594–5605.
Di Croce L, Raker AV, Corsaro M, Fazi F, Fanelli M, Faretta M et al. (2002). Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295: 1079–1082.
Dodge JE, Okano M, Dick F, Tsujimoto N, Chen T, Wang S et al. (2005). Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J Biol Chem 280: 17986–17991.
Ehrlich M . (2002). DNA methylation in cancer: too much, but also too little. Oncogene 21: 5400–5413.
Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G et al. (2006). Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ 13: 1238–1241.
Fanelli M, Fantozzi A, De Luca P, Caprodossi S, Matzusawa S, Lazar MA et al. (2004). The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila sina-mediated degradation of promyeloctic leukaemia protein and other tripartite motif proteins by the proteasome. J Biol Chem 279: 5374–5379.
Feinberg AP, Ohlsson R, Henikoff S . (2006). The epigenetic progenitor origin of human cancer. Nat Rev Genet 7: 21–33.
Feng J, Chang H, Li E, Fan G . (2005). Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 79: 734–746.
Gao Y, Guan M, Su B, Liu W, Xu M, Lu Y . (2004). Hypermethylation of the RASSF1A gene in gliomas. Clin Chim Acta 349: 173–179.
Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CMR et al. (1999). The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 96: 14412–14417.
Hassan AK, Norwood T, Gimelli G, Gartler SM, Hansen RS . (2001). Satellite 2 methylation pattern in normal and ICF syndrome cells and association of hypomethylation with advanced replication. Hum Genet 109: 452–462.
Jeanpierre M, Turleau C, Aurias A, Prieur M, Ledeist F, Fischer A et al. (1993). An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. Hum Mol Genet 2: 731–735.
Kang ES, Park CV, Chung JH . (2001). Dnmt3b, de novo DNA methyltransferase, interacts with SUMO-1 and Ubc9 through its N-terminal region and is subject to modification by SUMO-1. Biochem Bioph Res Commun 289: 862–868.
Lee C, Wevrick R, Fischer RB, Ferguson-Smith MA, Lin CC . (1997). Human centromeric DNAs. Hum Genet 100: 291–304.
Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK et al. (2001). Malignant glioma: genetics and biology of a grave matter. Gene Dev 15: 1311–1333.
Okano M, Bell DW, Haber DA, Li E . (1999). DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257.
Prosser J, Frommer M, Paul C, Vincent PC . (1986). Sequence relationship of three human satellite DNAs. J Mol Biol 187: 145–155.
Ricci-Vitiani L, Pedini F, Mollinari C, Condorelli G, Bonci D, Bez A et al. (2004). Absence of caspase 8 and high expression of PED protect primitive neural cells from cell death. J Exp Med 15: 1257–1266.
Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA et al. (1999). The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27: 2291–2298.
Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S . (2002). Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc Natl Acad Sci USA 99: 10060–10065.
Tsuda H, Takarabe T, Kanai Y, Fukutomi T, Hirohashi S . (2002). Correlation of DNA hypomethylation at pericentromeric heterochromatin regions of chromosomes 16 and 1 with histological features and chromosomal abnormalities of human breast carcinoma. Am J Pathol 161: 859–866.
Vilain A, Vogt N, Dutrillaux B, Malfoy B . (1999). DNA methylation and chromosome instability in breast cancer cell lines. FEBS Lett 460: 231–234.
Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M et al. (1999). Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402: 187–191.
Acknowledgements
We thank Dr Jae Hoon Chung for the Dnmt3b expressing vector and all friends of PGP's group of research. This study was supported by a grant of the Ministero della Salute – Progetto di Ricerca Finalizzata (prot. N. DGRST/CRS/RF-2003/1920).
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Fanelli, M., Caprodossi, S., Ricci-Vitiani, L. et al. Loss of pericentromeric DNA methylation pattern in human glioblastoma is associated with altered DNA methyltransferases expression and involves the stem cell compartment. Oncogene 27, 358–365 (2008). https://doi.org/10.1038/sj.onc.1210642
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DOI: https://doi.org/10.1038/sj.onc.1210642
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