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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., Oehme, I., Schroeder, C., Milde, T., Schier, M.C., Kopp-Schneider, A., Schulte, J.H., Fischer, M., De Preter, K., Pattyn, F., Castoldi, M., Muckenthaler, M.U., Kulozik, A.E., Westermann, F., 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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