title: Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death.
abstract: The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression.
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University of Göttingen, Göttingen, D-37077, Germany.|Department of Human Genetics, Hannover Medical School, Hannover, D-30625, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Beyer
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University of Göttingen, Göttingen, D-37077, Germany.
authors.forename: S K
authors.initials: SK
authors.lastname: Krönung
authors.affiliation: Department of Medical Statistics, University Göttingen, Göttingen, D-37033, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Leha
authors.affiliation: Primate Genetics Laboratory, German Primate Center, Göttingen, D-37077, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Walter
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University of Göttingen, Göttingen, D-37077, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D020077:Endogenous Retroviruses / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005854:Germ Cells; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020079:Terminal Repeat Sequences / Q000235:genetics*; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; C114109:TNFRSF21 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D006655:Histone Deacetylases; D002945:Cisplatin