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Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma

Ecker, Jonas ; Oehme, Ina ; Mazitschek, Ralph ; Korshunov, Andrey ; Kool, Marcel ; Hielscher, Thomas ; Kiss, Judit ; Selt, Florian ; Konrad, Carina ; Lodrini, Marco ; Deubzer, Hedwig E. ; von Deimling, Andreas ; Kulozik, Andreas E. ; Pfister, Stefan M. ; Witt, Olaf ; Milde, Till

In: Acta Neuropathologica Communications, 3 (UNSPECIFIED), Nr. 22. pp. 1-14. ISSN 2051-5960

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Download (1MB) | Lizenz: Creative Commons LizenzvertragTargeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma by Ecker, Jonas ; Oehme, Ina ; Mazitschek, Ralph ; Korshunov, Andrey ; Kool, Marcel ; Hielscher, Thomas ; Kiss, Judit ; Selt, Florian ; Konrad, Carina ; Lodrini, Marco ; Deubzer, Hedwig E. ; von Deimling, Andreas ; Kulozik, Andreas E. ; Pfister, Stefan M. ; Witt, Olaf ; Milde, Till underlies the terms of Creative Commons Attribution 3.0 Germany

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Abstract

Introduction: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Material and Methods: Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. Results: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. Conclusions: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration.

Item Type: Article
Journal or Publication Title: Acta Neuropathologica Communications
Volume: 3
Number: 22
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 18 Jan 2016 13:36
ISSN: 2051-5960
Page Range: pp. 1-14
Faculties / Institutes: Service facilities > Interdisziplinäres Zentrum für Neurowissenschaften
Service facilities > German Cancer Research Center (DKFZ)
Medizinische Fakultät Heidelberg > Universitätskinderklinik
Medizinische Fakultät Heidelberg > Pathologisches Institut
Subjects: 610 Medical sciences Medicine
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