title: The seminoma cell line TCam-2 is sensitive to HDAC inhibitor depsipeptide but tolerates various other chemotherapeutic drugs and loss of NANOG expression.
abstract: Seminomas and embryonal carcinomas (EC) are both type II germ cell tumor (GCT) entities and develop from the same precursor lesion (carcinoma-in situ, CIS). However, they show significant differences in growth behavior, differentiation potential, and gene expression. Although ECs are prone to differentiate into all three germ layers and give rise to the non-seminomatous GCT entities teratoma, choriocarcinoma, and yolk-sac tumor, differentiation of seminomas to these entities is only rarely observed. This might reflect the ability of seminomas to actively inhibit differentiation processes evoked by environmental cues. Also, it is not known why CIS gives rise to seminoma in some patients and to non-seminoma in the others. Here, we treated the seminoma-like cell line TCam-2 with the HDAC-inhibitor Depsipeptide, the global demethylating agent 5-aza-2'-deocycytidine, all-trans retinoic acid and the monaminooxidase inhibitor Tranylcipromine and also used knock down approaches to reduce expression of the pluripotency marker NANOG and/or the inhibitor of primordial germ cell differentiation TFAP2C. We found that TCam-2 cells induce apoptosis when treated with Depsipeptide (> 10 nM) but are resistant to treatments with 5-aza-2'-deocycytidine, all-trans retinoic acid and Tranylcipromine, highlighting Depsi as a treatment option for seminomas. We show that TCam-2 cells up-regulate endoderm- and throphectoderm-associated genes after down-regulation of NANOG expression; however, morphologically no indications of differentiation could be found. Instead, we observed up-regulation of OCT3/4 and SOX17 in TCam-2-NANOG knockdown and speculate that this compensates for the loss of the NANOG protein. Hence, NANOG is not a primary target gene responsible for the inhibition of differentiation in seminomas.
authors: Department of Developmental Pathology, Institute of Pathology, University of Bonn, Bonn, Germany.
authors: Daniel
authors: D
authors: Nettersheim
authors: Ad
authors: A
authors: Gillis
authors: Katharina
authors: K
authors: Biermann
authors: Leendert H J
authors: LH
authors: Looijenga
authors: Hubert
authors: H
authors: Schorle
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D000077209:Decitabine; D047630:Depsipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004707:Endoderm / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics; D018239:Seminoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050656:Transcription Factor AP-2 / Q000235:genetics; D014191:Tranylcypromine / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D014191:Tranylcypromine; D014212:Tretinoin; D000077209:Decitabine; D006655:Histone Deacetylases; D001374:Azacitidine