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Int. J. Mol. Sci. 2013, 14(4), 7492-7505; doi:10.3390/ijms14047492

Epigenetic Silencing of DKK3 in Medulloblastoma

15,*  and 16
1 Department of Experimental Medicine (DIMES), University of Genoa-IRCCS A.O.U. San Martino–IST National Cancer Research Institute, Genoa 16132, Italy 2 Laboratory of Tumor Genetics and Epigenetics, IRCCS A.O.U. San Martino–IST National Cancer Research Institute, Genoa 16132, Italy 3 Center of Physiopathology of Human Reproduction, Obstetrics and Gynecology Unit, IRCCS A.O.U. San Martino–IST National Cancer Research Institute, Genoa 16132, Italy 4 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany 5 Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg 69120, Germany 6 CNRS-LAMSADE Laboratoire d'Analyse et Modélisation de Systèmes pour l'Aide à la decision Paris 75775, France 7 Université Paris-Dauphine, Paris 75775, France 8 Developmental & Stem Cell Biology Program, the Hospital for Sick Children, Toronto M5G 1X8, Canada 9 Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 10 Division of Biostatistics German Cancer Research Center (DKFZ), Heidelberg 69120, Germany 11 Division of Pediatric Oncology, Catholic University, Rome 00198, Italy 12 CEINGE, Centro di Ingegneria Genetica e Biotecnologia Avanzate, Naples 80145, Italy 13 Pediatric Neurosurgery, Santobono-Pausilipon Children's Hospital, Naples 80122, Italy 14 Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Cologne 50924, Germany 15 Laboratory of Neuroblastoma, Onco/Hematology Laboratory Department SDB University of Padua, Pediatric Research Institute, Padua 35127, Italy 16 Lung Cancer Unit IRCSS San Martino Hospital-IST National Cancer Research Institute, Genoa 16132, Italy These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 6 February 2013 / Revised: 25 March 2013 / Accepted: 27 March 2013 / Published: 8 April 2013
(This article belongs to the Special Issue Advances in Cancer Diagnosis)
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Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. We studied the expression of Dickkopf (DKK) 1–4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.001). Since copy number aberrations targeting the DKK3 locus (11p15.3) are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively) excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA), a potent inhibitor of histone deacetylases (HDAC), was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.
Keywords: medulloblastoma; Wnt antagonists; DKK family; DKK3 downregulation; histone deacetylase; TSA medulloblastoma; Wnt antagonists; DKK family; DKK3 downregulation; histone deacetylase; TSA
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Valdora, F.; Banelli, B.; Stigliani, S.; Pfister, S.M.; Moretti, S.; Kool, M.; Remke, M.; Bai, A.H.; Brigati, C.; Hielscher, T.; Romani, M.; Servidei, T.; Zollo, M.; Cinalli, G.; Oberthuer, A.; Tonini, G.P.; Coco, S. Epigenetic Silencing of DKK3 in Medulloblastoma. Int. J. Mol. Sci. 2013, 14, 7492-7505.

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