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Epigenetic Silencing of DKK3 in Medulloblastoma
Department of Experimental Medicine (DIMES), University of Genoa-IRCCS A.O.U. San Martino–IST National Cancer Research Institute, Genoa 16132, Italy
Laboratory of Tumor Genetics and Epigenetics, IRCCS A.O.U. San Martino–IST National Cancer Research Institute, Genoa 16132, Italy
Center of Physiopathology of Human Reproduction, Obstetrics and Gynecology Unit, IRCCS A.O.U. San Martino–IST National Cancer Research Institute, Genoa 16132, Italy
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Heidelberg 69120, Germany
CNRS-LAMSADE Laboratoire d'Analyse et Modélisation de Systèmes pour l'Aide à la decision Paris 75775, France
Université Paris-Dauphine, Paris 75775, France
Developmental & Stem Cell Biology Program, the Hospital for Sick Children, Toronto M5G 1X8, Canada
Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
Division of Biostatistics German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Division of Pediatric Oncology, Catholic University, Rome 00198, Italy
CEINGE, Centro di Ingegneria Genetica e Biotecnologia Avanzate, Naples 80145, Italy
Pediatric Neurosurgery, Santobono-Pausilipon Children's Hospital, Naples 80122, Italy
Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Cologne 50924, Germany
Laboratory of Neuroblastoma, Onco/Hematology Laboratory Department SDB University of Padua, Pediatric Research Institute, Padua 35127, Italy
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; in revised form: 25 March 2013 / Accepted: 27 March 2013 / Published: 8 April 2013
Abstract: 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
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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.
Valdora F, Banelli B, Stigliani S, Pfister SM, Moretti S, Kool M, Remke M, Bai AH, Brigati C, Hielscher T, Romani M, Servidei T, Zollo M, Cinalli G, Oberthuer A, Tonini GP, Coco S. Epigenetic Silencing of DKK3 in Medulloblastoma. International Journal of Molecular Sciences. 2013; 14(4):7492-7505.
Valdora, Francesca; Banelli, Barbara; Stigliani, Sara; Pfister, Stefan M.; Moretti, Stefano; Kool, Marcel; Remke, Marc; Bai, Alfa H.; Brigati, Claudio; Hielscher, Thomas; Romani, Massimo; Servidei, Tiziana; Zollo, Massimo; Cinalli, Giuseppe; Oberthuer, André; Tonini, Gian P.; Coco, Simona. 2013. "Epigenetic Silencing of DKK3 in Medulloblastoma." Int. J. Mol. Sci. 14, no. 4: 7492-7505.