title: LTR12 promoter activation in a broad range of human tumor cells by HDAC inhibition.
abstract: A considerable proportion of the human genome consists of transposable elements, including the long terminal repeats (LTRs) of endogenous retroviruses. During evolution, such LTRs were occasionally inserted upstream of protein-coding genes, contributing to their regulation. We previously identified the LTR12 from endogenous retrovirus 9 (ERV9) as a regulator of proapoptotic genes such as TP63 or TNFRSF10B. The promoter activity of LTR12 is largely confined to the testes, silenced in testicular carcinoma, but reactivated in testicular cancer cells by broad-range histone deacetylase (HDAC) inhibitors. Here we show that inhibition of HDAC1-3 is sufficient for LTR12 activation. Importantly, HDAC inhibitors induce LTR12 activity not only in testicular cancer cells, but also in cells derived from many additional tumor species. Finally, we characterize the transcription factor NF-Y as a mediator of LTR12 promoter activity and HDAC inhibitor-induced apoptosis, in the context of widespread genomic binding of NF-Y to specific LTR12 sequences. Thus, HDAC inhibitor-driven LTR12 activation represents a generally applicable means to induce proapoptotic genes in human cancer cells.
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center, University of Göttingen, Göttingen, Germany.
authors.forename: Sonja K
authors.initials: SK
authors.lastname: Krönung
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center, University of Göttingen, Göttingen, Germany.|Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Beyer
authors.affiliation: Dipartimento di Bioscienze, UniversitàdegliStudi di Milano, Via Celoria, Milan, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Chiaramonte
authors.affiliation: Dipartimento di Bioscienze, UniversitàdegliStudi di Milano, Via Celoria, Milan, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Dolfini
authors.affiliation: Dipartimento di Bioscienze, UniversitàdegliStudi di Milano, Via Celoria, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mantovani
authors.affiliation: Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center, University of Göttingen, Göttingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D045744:Cell Line, Tumor; D020077:Endogenous Retroviruses; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000235:genetics*; D020079:Terminal Repeat Sequences / Q000235:genetics*
chemical_list: D056572:Histone Deacetylase Inhibitors
keywords: factor binding; genome-wide gene expression analysis