TY - JOUR
T1 - Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma
AU - Ecker, Jonas
AU - Oehme, Ina
AU - Mazitschek, Ralph
AU - Korshunov, Andrey
AU - Kool, Marcel
AU - Hielscher, Thomas
AU - Kiss, Judit
AU - Selt, Florian
AU - Konrad, Carina
AU - Lodrini, Marco
AU - Deubzer, Hedwig E.
AU - von Deimling, Andreas
AU - Kulozik, Andreas E.
AU - Pfister, Stefan M.
AU - Witt, Olaf
AU - Milde, Till
N1 - Funding Information:
This work was supported by the MYCNet (BMBF), and the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung). JE was supported by Talents in Medicine program of University Hospital Heidelberg and by The German National Academic Foundation (Studienstiftung des deutschen Volkes). IO was supported by the BMWi through SME to IO und DFG (OE 542/2-1) 2014 to IO. RM was supported by the National Institute of Health (P50CA086355).
PY - 2015/4/3
Y1 - 2015/4/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016650522&partnerID=8YFLogxK
U2 - 10.1186/s40478-015-0201-7
DO - 10.1186/s40478-015-0201-7
M3 - Article
C2 - 25853389
AN - SCOPUS:85016650522
SN - 2051-5960
VL - 3
SP - 22
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
ER -