title: Transcription factor BORIS (Brother of the Regulator of Imprinted Sites) directly induces expression of a cancer-testis antigen, TSP50, through regulated binding of BORIS to the promoter.
abstract: Cancer-testis antigens (CTAs) are normally expressed in testis but are aberrantly expressed in a variety of cancers with varying frequency. More than 100 proteins have been identified as CTA including testes-specific protease 50 (TSP50) and the testis-specific paralogue of CCCTC-binding factor, BORIS (brother of the regulator of imprinted sites). Because many CTAs are considered as excellent targets for tumor immunotherapy, understanding the regulatory mechanisms governing their expression is important. In this study we demonstrate that BORIS is directly responsible for the transcriptional activation of TSP50. We found two BORIS binding sites in the TSP50 promoter that are highly conserved between mouse and human. Mutations of the binding sites resulted in loss of BORIS binding and the ability of BORIS to activate the promoter. However, although expression of BORIS was essential, it was not sufficient for high expression of TSP50 in cancer cells. Further studies showed that binding of BORIS to the target sites was methylation-independent but was diminished by nucleosomal occupancy consistent with the findings that high expression of TSP50 was associated with increased DNase I sensitivity and high BORIS occupancy of the promoter. These findings indicate that BORIS-induced expression of TSP50 is governed by accessibility and binding of BORIS to the promoter. To our knowledge this is the first report of regulated expression of one CTA by another to be validated in a physiological context.
authors.affiliation: Laboratory of Immunopathology, NIAID, National Institutes of Health, Rockville, Maryland 20852, USA.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Kosaka-Suzuki
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Elena M
authors.initials: EM
authors.lastname: Pugacheva
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vostrov
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Dmitri
authors.initials: D
authors.lastname: Loukinov
authors.forename: Victor
authors.initials: V
authors.lastname: Lobanenkov
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: C456540:CTCFL protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D012697:Serine Endopeptidases; C446379:testis-specific protease 50