title: Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival.
abstract: The number of long-term survivors of high-risk neuroblastoma remains discouraging, with 10-year survival as low as 20%, despite decades of considerable international efforts to improve outcome. Major obstacles remain and include managing resistance to induction therapy, which causes tumor progression and early death in high-risk patients, and managing chemotherapy-resistant relapses, which can occur years after the initial diagnosis. Identifying and validating novel therapeutic targets is essential to improve treatment. Delineating and deciphering specific functions of single histone deacetylases in neuroblastoma may support development of targeted acetylome-modifying therapeutics for patients with molecularly defined high-risk neuroblastoma profiles. We show here that HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs. Genes necessary for mitotic cell cycle progression and cell division were most prominently enriched in at least two of three time points in whole-genome expression data combined from two cell systems, and all nine genes in these functional categories were strongly repressed, including CENPA, KIF14, KIF23 and RACGAP1. Enforced expression of one selected candidate, RACGAP1, partially rescued the induction of apoptosis caused by HDAC11 depletion. High-level expression of all nine genes in primary neuroblastomas significantly correlated with unfavorable overall and event-free survival in patients, suggesting a role in mediating the more aggressive biological and clinical phenotype of these tumors. Our study identified a group of cell cycle-promoting genes regulated by HDAC11, being both predictors of unfavorable patient outcome and essential for tumor cell viability. The data indicate a significant role of HDAC11 for mitotic cell cycle progression and survival of MYCN-amplified neuroblastoma cells, and suggests that HDAC11 could be a valuable drug target.
authors.affiliation: Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.|Department of Pediatric Hematology and Oncology, University of Heidelberg, INF 430, Heidelberg 69120, Germany.|Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF 280, Heidelberg 69120, Germany.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Thole
authors.affiliation: Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.|Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF 280, Heidelberg 69120, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Lodrini
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF 280, Heidelberg 69120, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Fabian
authors.affiliation: Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.|Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF 280, Heidelberg 69120, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wuenschel
authors.affiliation: Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pfeil
authors.affiliation: Department of Biostatistics, German Cancer Research Center (DKFZ), INF581, Heidelberg 69120, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-1277-310X
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Department of Biostatistics, German Cancer Research Center (DKFZ), INF581, Heidelberg 69120, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, J. W. Goethe University Hospital Frankfurt, Korntur Str. 3a, Frankfurt am Main 60528, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heinicke
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, J. W. Goethe University Hospital Frankfurt, Korntur Str. 3a, Frankfurt am Main 60528, Germany.|German Cancer Consortium (DKTK), INF 280, Heidelberg 69120, Germany.|German Cancer Research Center (DKFZ), INF 280, Heidelberg 69120, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: Department of Pediatric Hematology and Oncology, University of Heidelberg, INF 430, Heidelberg 69120, Germany.|Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF 280, Heidelberg 69120, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.affiliation: Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: Department of Pediatric Hematology and Oncology, University of Cologne, Kerpener Str. 62, Cologne 50937, Germany.|Department of Children and Adolescent Medicine, Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, Cologne 50931, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.|Department of Pediatric Hematology and Oncology, University of Heidelberg, INF 430, Heidelberg 69120, Germany.|Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), INF 280, Heidelberg 69120, Germany.|Junior Neuroblastoma Research Group, Experimental and Clinical Research Center (ECRC) of the Max-Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Community and the Charité-University Medicine Berlin, Lindenberger Weg 80, Berlin 13125, Germany.
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D018572:Disease-Free Survival; D015870:Gene Expression / Q000235:genetics; D018816:Genes, cdc / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism*
chemical_list: C462506:HDAC11 protein, human; D006655:Histone Deacetylases