title: MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.
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.
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. m.lodrini@dkfz.de
authors.forename: Marco
authors.initials: M
authors.lastname: Lodrini
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.forename: Christina
authors.initials: C
authors.lastname: Schroeder
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Marie C
authors.initials: MC
authors.lastname: Schier
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.forename: Filip
authors.initials: F
authors.lastname: Pattyn
authors.forename: Mirco
authors.initials: M
authors.lastname: Castoldi
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
chemical_list: D056572:Histone Deacetylase Inhibitors; C533449:MIRN183 microRNA, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2