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MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma

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Item Type:Article
Title:MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma
Creators Name:Lodrini, M. and Oehme, I. and Schroeder, C. and Milde, T. and Schier, M.C. and Kopp-Schneider, A. and Schulte, J.H. and Fischer, M. and De Preter, K. and Pattyn, F. and Castoldi, M. and Muckenthaler, M.U. and Kulozik, A.E. and Westermann, F. and Witt, O. and Deubzer, H.E.
Abstract:MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
Keywords:Cell Death, Genetic Promoter Regions, Histone Deacetylase 2, Histone Deacetylase Inhibitors, MicroRNAs, N-Myc Proto-Oncogene Protein, Neuroblastoma, Nuclear Proteins, Oncogene Proteins, Signal Transduction, Tumor Cell Line, Animals, Mice
Source:Nucleic Acids Research
Publisher:Oxford University Press
Page Range:6018-6033
Date:1 July 2013
Official Publication:https://doi.org/10.1093/nar/gkt346
PubMed:View item in PubMed

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