title: The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells.
abstract: Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leukemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3.
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy; Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zampieri
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy; Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciccarone
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Department of Molecular Medicine, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.affiliation: Institute of Molecular Biology & Pathology CNR, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Passananti
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Nocchia
authors.affiliation: Department of Molecular Medicine, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
authors.affiliation: Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy; Department of Molecular Medicine, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy. Electronic address: isabella.screpanti@uniroma1.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy & Medicine, Sapienza University of Rome, Rome, Italy; Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy. Electronic address: caiafa@bce.uniroma1.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Caiafa
mesh_terms: D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000502:physiology*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011401:Promoter Regions, Genetic; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*
chemical_list: C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: Cancer testis antigen; Chromatin; DNA/histone methylation; Oncogene; T cell acute lymphoblastic leukemia