Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma
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Author
Ecker, Jonas
Oehme, Ina
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
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1186/s40478-015-0201-7Metadata
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Ecker, J., I. Oehme, R. Mazitschek, A. Korshunov, M. Kool, T. Hielscher, J. Kiss, et al. 2015. “Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma.” Acta Neuropathologica Communications 3 (1): 22. doi:10.1186/s40478-015-0201-7. http://dx.doi.org/10.1186/s40478-015-0201-7.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. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0201-7) contains supplementary material, which is available to authorized users.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382927/pdf/Terms of Use
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