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@ARTICLE{Thole:120551,
author = {T. Thole$^*$ and M. Lodrini$^*$ and J. Fabian$^*$ and J.
Wuenschel$^*$ and S. Pfeil and T. Hielscher and A.
Kopp-Schneider$^*$ and U. Heinicke and S. Fulda and O.
Witt$^*$ and A. Eggert and M. Fischer and H. E. Deubzer$^*$},
title = {{N}euroblastoma cells depend on {HDAC}11 for mitotic cell
cycle progression and survival.},
journal = {Cell death $\&$ disease},
volume = {8},
number = {3},
issn = {2041-4889},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2017-00980},
pages = {e2635},
year = {2017},
abstract = {The number of long-term survivors of high-risk
neuroblastoma remains discouraging, with 10-year survival as
low as $20\%,$ despite decades of considerable international
efforts to improve outcome. Major obstacles remain and
include managing resistance to induction therapy, which
causes tumor progression and early death in high-risk
patients, and managing chemotherapy-resistant relapses,
which can occur years after the initial diagnosis.
Identifying and validating novel therapeutic targets is
essential to improve treatment. Delineating and deciphering
specific functions of single histone deacetylases in
neuroblastoma may support development of targeted
acetylome-modifying therapeutics for patients with
molecularly defined high-risk neuroblastoma profiles. We
show here that HDAC11 depletion in MYCN-driven neuroblastoma
cell lines strongly induces cell death, mostly mediated by
apoptotic programs. Genes necessary for mitotic cell cycle
progression and cell division were most prominently enriched
in at least two of three time points in whole-genome
expression data combined from two cell systems, and all nine
genes in these functional categories were strongly
repressed, including CENPA, KIF14, KIF23 and RACGAP1.
Enforced expression of one selected candidate, RACGAP1,
partially rescued the induction of apoptosis caused by
HDAC11 depletion. High-level expression of all nine genes in
primary neuroblastomas significantly correlated with
unfavorable overall and event-free survival in patients,
suggesting a role in mediating the more aggressive
biological and clinical phenotype of these tumors. Our study
identified a group of cell cycle-promoting genes regulated
by HDAC11, being both predictors of unfavorable patient
outcome and essential for tumor cell viability. The data
indicate a significant role of HDAC11 for mitotic cell cycle
progression and survival of MYCN-amplified neuroblastoma
cells, and suggests that HDAC11 could be a valuable drug
target.},
cin = {G340 / C060 / L101 / L501 / L201},
ddc = {570},
cid = {I:(DE-He78)G340-20160331 / I:(DE-He78)C060-20160331 /
I:(DE-He78)L101-20160331 / I:(DE-He78)L501-20160331 /
I:(DE-He78)L201-20160331},
pnm = {317 - Translational cancer research (POF3-317)},
pid = {G:(DE-HGF)POF3-317},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:28252645},
pmc = {pmc:PMC5386552},
doi = {10.1038/cddis.2017.49},
url = {https://inrepo02.dkfz.de/record/120551},
}