title: Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Jonas
authors: J
authors: Ecker
authors: Ina
authors: I
authors: Oehme
authors: Ralph
authors: R
authors: Mazitschek
authors: Andrey
authors: A
authors: Korshunov
authors: Marcel
authors: M
authors: Kool
authors: Thomas
authors: T
authors: Hielscher
authors: Judit
authors: J
authors: Kiss
authors: Florian
authors: F
authors: Selt
authors: Carina
authors: C
authors: Konrad
authors: Marco
authors: M
authors: Lodrini
authors: Hedwig E
authors: HE
authors: Deubzer
authors: Andreas
authors: A
authors: von Deimling
authors: Andreas E
authors: AE
authors: Kulozik
authors: Stefan M
authors: SM
authors: Pfister
authors: Olaf
authors: O
authors: Witt
authors: Till
authors: T
authors: Milde
mesh_terms: D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D005784:Gene Amplification / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008527:Medulloblastoma / Q000145:classification* / Q000201:enzymology* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D020169:Caspases; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2