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10.18632/oncotarget.11647

http://scihub22266oqcxt.onion/10.18632/oncotarget.11647
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suck abstract from ncbi


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pmid27572311
      Oncotarget 2016 ; 7 (46 ): 74931-74946
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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]
  • |Dose-Response Relationship, Drug [MESH]
  • |Dual Specificity Phosphatase 1/*metabolism [MESH]
  • |Gene Expression Regulation, Neoplastic [MESH]
  • |Gene Regulatory Networks [MESH]
  • |Histone Deacetylase Inhibitors/pharmacology [MESH]
  • |Histone Deacetylases/metabolism [MESH]
  • |Histones/metabolism [MESH]
  • |Humans [MESH]
  • |Models, Biological [MESH]
  • |Neoplasms, Germ Cell and Embryonal/drug therapy/genetics/*metabolism [MESH]
  • |Nuclear Proteins/*metabolism [MESH]


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