title: A signaling cascade including ARID1A, GADD45B and DUSP1 induces apoptosis and affects the cell cycle of germ cell cancers after romidepsin treatment.
abstract: 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.
authors: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors: Daniel
authors: D
authors: Nettersheim
authors: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors: Sina
authors: S
authors: Jostes
authors: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors: Martin
authors: M
authors: Fabry
authors: Tumor- and Breast Center ZeTuP Silberturm, St. Gallen, Switzerland.
authors: Friedemann
authors: F
authors: Honecker
authors: Harvard Medical School, Department of Pediatrics, Boston, Massachusetts, USA.
authors: Valerie
authors: V
authors: Schumacher
authors: Institute of Pathology, University Medical School, Bonn, Germany.
authors: Jutta
authors: J
authors: Kirfel
authors: Institute of Pathology, University Medical School, Bonn, Germany.
authors: Glen
authors: G
authors: Kristiansen
authors: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors: Hubert
authors: H
authors: Schorle
mesh_terms: D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D000903:Antibiotics, Antineoplastic; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D054638:Dual Specificity Phosphatase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; C112476:ARID1A protein, human; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C087123:romidepsin; C517019:DUSP1 protein, human
keywords: ARID1A; germ cell cancer; histone deactylase inhibitor; romidepsin; therapy