title: Loss of the Notch effector RBPJ promotes tumorigenesis.
abstract: Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis.
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada Experimental Medicine Program and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, British Columbia, Canada.
authors.forename: Iva
authors.initials: I
authors.lastname: Kulic
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Robertson
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Jennifer H E
authors.initials: JH
authors.lastname: Baker
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Winnie
authors.initials: W
authors.lastname: Mok
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: Fuller
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Michèle
authors.initials: M
authors.lastname: Fournier
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Nelson
authors.initials: N
authors.lastname: Wong
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Vennie
authors.initials: V
authors.lastname: Chou
authors.affiliation: Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich, CH-8057 Zurich, Switzerland Institute of Molecular Life Sciences and SIB Swiss Institute of Bioinformatics, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Robinson
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Chun
authors.affiliation: Experimental Medicine Program and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, British Columbia, Canada.
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.affiliation: Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Kempkes
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Thomson
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Marra
authors.affiliation: Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada Experimental Medicine Program and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, British Columbia, Canada Experimental Medicine Program and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, British Columbia, Canada akarsan@bcgsc.ca.
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D000107:Acetylation; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D006657:Histones; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C489427:MYC protein, human; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; C497570:RBPJ protein, human; D051880:Receptors, Notch