title: The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo.
abstract: Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20-40 years) and are classified as seminoma or non-seminoma. TGCTs are commonly treated by orchiectomy and chemo- or radiotherapy. However, a subset of metastatic non-seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumour therapy, which interferes with the function of 'bromodomain and extraterminal (BET)' proteins. JQ1-treated TGCT cell lines display up-regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down-regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma-like TCam-2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.
authors.affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors.forename: Sina
authors.initials: S
authors.lastname: Jostes
authors.affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nettersheim
authors.affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fellermeyer
authors.affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors.forename: François
authors.initials: F
authors.lastname: Hafezi
authors.affiliation: Breast and Tumor Center, ZeTup Silberturm, St Gallen, Switzerland.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.affiliation: Department of Urology, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Schumacher
authors.affiliation: Institute of Innate Immunity, Department of Structural Immunology, University Medical School, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.affiliation: Institute of Pathology, University Medical School, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Pathology, Department of Developmental Pathology, University Medical School, Bonn, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000008:administration & dosage*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D014230:Triazoles
keywords: HDAC inhibitor; JQ1; bromodomain proteins; cisplatin resistance; differentiation; epigenetic therapy; germ cell cancer; pluripotency; romidepsin; xenografts