Abstract
IntroductionMedulloblastoma (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 MethodsExpression 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.ResultsHDAC2 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0201-7) contains supplementary material, which is available to authorized users.
Highlights
Medulloblastoma (MB) is the most frequent malignant brain tumor in children
MYC amplified medulloblastomas display differential expression of class I histone deacetylase (HDAC) We have previously shown that differential expression of HDAC family members occur in medulloblastoma
Since target expression in the respective tissue is a prerequisite for targeted treatment, we examined the expression of class I HDACs in primary tissues
Summary
Medulloblastoma (MB) is the most frequent malignant brain tumor in children. We explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. Medulloblastomas (MB) are the most frequent malignant brain tumors in children, with approximately 60 and 300 newly diagnosed cases per year in Germany and the US, respectively [1]. Each molecular subgroup can be divided further into different subtypes based on characteristic molecular aberrations, with different clinical courses in SHH, Group 3 and Group 4 [8], strongly suggesting additional biological heterogeneity in each subgroup. Several mechanisms of structural variation are recurrent in Group 3 and Group 4 tumors, including somatic copy number alterations, chromothripsis and tetraploidy [13,14], as well as a newly recognized mechanism termed enhancer hijacking that leads to aberrant oncogene expression [10]
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