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

Overview of attention for article published in Acta Neuropathologica Communications, April 2015
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Title
Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma
Published in
Acta Neuropathologica Communications, April 2015
DOI 10.1186/s40478-015-0201-7
Pubmed ID
Authors

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

Abstract

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. 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. 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. 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.

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Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 78 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 1%
Germany 1 1%
Unknown 76 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 21 27%
Student > Master 10 13%
Student > Bachelor 9 12%
Researcher 9 12%
Student > Doctoral Student 4 5%
Other 11 14%
Unknown 14 18%
Readers by discipline Count As %
Medicine and Dentistry 20 26%
Biochemistry, Genetics and Molecular Biology 18 23%
Agricultural and Biological Sciences 12 15%
Chemistry 6 8%
Pharmacology, Toxicology and Pharmaceutical Science 3 4%
Other 7 9%
Unknown 12 15%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 April 2015.
All research outputs
#20,273,512
of 22,805,349 outputs
Outputs from Acta Neuropathologica Communications
#1,302
of 1,372 outputs
Outputs of similar age
#223,611
of 264,201 outputs
Outputs of similar age from Acta Neuropathologica Communications
#13
of 15 outputs
Altmetric has tracked 22,805,349 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,372 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.9. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 15 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.