title: BORIS binding to the promoters of cancer testis antigens, MAGEA2, MAGEA3, and MAGEA4, is associated with their transcriptional activation in lung cancer.
abstract: OBJECTIVE
  Aim of this study was to determine whether BORIS (Brother of the Regulator of Imprinted Sites) is a regulator of MAGEA2, MAGEA3, and MAGEA4 genes in lung cancer.
  
  
  METHODS
  Changes in expression of MAGEA genes upon BORIS induction/knockdown were studied. Recruitment of BORIS and changes in histone modifications at their promoters upon BORIS induction were analyzed. Luciferase assays were used to study their activation by BORIS. Changes in methylation at these promoters upon BORIS induction were evaluated.
  
  
  RESULTS
  Alteration of BORIS expression by induction/knockdown directly correlated with expression of MAGEA genes. BORIS was enriched at their promoters in H1299 cells, which show high expression of these cancer testis antigens (CTA), compared with normal human bronchial epithelial (NHBE) cells which show low expression of the target CTAs. BORIS induction in A549 cells resulted in increased amounts of BORIS and activating histone modifications at their promoters along with a corresponding increase in their expression. Similarly, BORIS binding at these promoters in H1299 correlates with enrichment of activating modifications, whereas absence of BORIS binding in NHBE is associated with enrichment of repressive marks. BORIS induction of MAGEA3 was associated with promoter demethylation, but no methylation changes were noted with activation of MAGEA2 and MAGEA4.
  
  
  CONCLUSIONS
  These data suggest that BORIS positively regulates these CTAs by binding and inducing a shift to a more open chromatin conformation with promoter demethylation for MAGEA3 or independent of promoter demethylation in case of MAGEA2 and MAGEA4 and may be a key effector involved in their derepression in lung cancer.
authors.affiliation: Department of Otolaryngology-Head, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Bhan
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Negi
authors.forename: Chunbo
authors.initials: C
authors.lastname: Shao
authors.forename: Chad A
authors.initials: CA
authors.lastname: Glazer
authors.forename: Alice
authors.initials: A
authors.lastname: Chuang
authors.forename: Daria A
authors.initials: DA
authors.lastname: Gaykalova
authors.forename: Wenyue
authors.initials: W
authors.lastname: Sun
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Ha
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Califano
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding
chemical_list: D000951:Antigens, Neoplasm; C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; D006657:Histones