title: CTCF and BORIS regulate Rb2/p130 gene transcription: a novel mechanism and a new paradigm for understanding the biology of lung cancer.
abstract: Although innumerable investigations regarding the biology of lung cancer have been carried out, many aspects thereof remain to be addressed, including the role played by the retinoblastoma-related protein Rb2/p130 during the evolution of this disease. Here we report novel findings on the mechanisms that control Rb2/p130 gene expression in lung fibroblasts and characterize the effects of Rb2/p130 deregulation on the proliferative features of lung cancer cells. We revealed for the first time that in lung fibroblasts the expression of Rb2/p130 gene is directly controlled by the chromatin insulator CCCTC-binding factor, CTCF, which by binding to the Rb2/p130 gene promoter induces, and/or maintains, a specific local chromatin organization that in turn governs the transcriptional activity of Rb2/p130 gene. However, in lung cancer cells the activity of CTCF in controlling Rb2/p130 gene expression is impaired by BORIS, a CTCF-paralogue, which by binding to the Rb2/p130 gene could trigger changes in the chromatin asset established by CTCF, thereby affecting CTCF regulatory activity on Rb2/p130 transcription. These studies not only provide essential basic insights into the molecular mechanisms that control Rb2/p130 gene expression in lung cancer, but also offer a potential paradigm for the actions of other activators and/or corepressors, such as CTCF and BORIS, that could be crucial in explaining how alterations in the mechanism regulating Rb2/p130 gene expression may accelerate the progression of lung tumors, or favor the onset of recurrence after cancer treatment.
authors.affiliation: Sbarro Health Research Organization, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Fiorentino
authors.forename: Marcella
authors.initials: M
authors.lastname: Macaluso
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Miranda
authors.forename: Micaela
authors.initials: M
authors.lastname: Montanari
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Luigi
authors.initials: L
authors.lastname: Bagella
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D045584:Chromosome Positioning / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D016366:Open Reading Frames / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D050717:Retinoblastoma-Like Protein p130