期刊
NUCLEIC ACIDS RESEARCH
卷 41, 期 12, 页码 6018-6033出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt346
关键词
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资金
- Bundesministerium fur Bildung und Forschung (BMBF) through NGFNplus
- Bundesministerium fur Bildung und Forschung (BMBF) through MYC-NET
- Bundesministerium fur Bildung und Forschung (BMBF) through CancerSys
- European Union
- Research Foundation-Flanders (FWO)
- German Cancer Research Center (DKFZ)
- University of Heidelberg
- Wilhelm Sander Foundation
- Federal Ministry of Economics and Technology, Central Innovation Programme SME
- BMBF
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.
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