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2016 ; 7
(46
): 74931-74946
Nephropedia Template TP
gab.com Text
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A signaling cascade including ARID1A, GADD45B and DUSP1 induces apoptosis and
affects the cell cycle of germ cell cancers after romidepsin treatment
#MMPMID27572311
Nettersheim D
; Jostes S
; Fabry M
; Honecker F
; Schumacher V
; Kirfel J
; Kristiansen G
; Schorle H
Oncotarget
2016[Nov]; 7
(46
): 74931-74946
PMID27572311
show ga
In Western countries, the incidence of testicular germ cell cancers (GCC) is
steadily rising over the last decades. Mostly, men between 20 and 40 years of age
are affected. In general, patients suffering from GCCs are treated by orchiectomy
and radio- or chemotherapy. Due to resistance mechanisms, intolerance to the
therapy or denial of chemo- / radiotherapy by the patients, GCCs are still a
lethal threat, highlighting the need for alternative treatment strategies.In this
study, we revealed that germ cell cancer cell lines are highly sensitive to the
histone deacetylase inhibitor romidepsin in vitro and in vivo, highlighting
romidepsin as a potential therapeutic option for GCC patients.Romidepsin-mediated
inhibition of histone deacetylases led to disturbances of the chromatin
landscape. This resulted in locus-specific histone-hyper- or hypoacetylation. We
found that hypoacetylation at the ARID1A promotor caused repression of the
SWI/SNF-complex member ARID1A. In consequence, this resulted in upregulation of
the stress-sensors and apoptosis-regulators GADD45B, DUSP1 and CDKN1A.
RNAi-driven knock down of ARID1A mimicked in parts the effects of romidepsin,
while CRISPR/Cas9-mediated deletion of GADD45B attenuated the romidepsin-provoked
induction of apoptosis and cell cycle alterations.We propose a signaling cascade
involving ARID1A, GADD45B and DUSP1 as mediators of the romidepsin effects in GCC
cells.
|*Apoptosis
[MESH]
|*Cell Cycle
[MESH]
|*Signal Transduction
[MESH]
|Acetylation
[MESH]
|Antibiotics, Antineoplastic/pharmacology/therapeutic use
[MESH]
|Antigens, Differentiation/*metabolism
[MESH]
|Cell Line, Tumor
[MESH]
|Cell Proliferation/drug effects
[MESH]
|Cell Survival/drug effects
[MESH]
|DNA-Binding Proteins
[MESH]
|Depsipeptides/pharmacology/therapeutic use
[MESH]