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Loss of the Notch effector RBPJ promotes tumorigenesis.
J Exp Med. 2015 Jan 12; 212(1):37-52.JE

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+Show Affiliations

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.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.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.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.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.Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.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.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.Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25512468

Citation

Kulic, Iva, et al. "Loss of the Notch Effector RBPJ Promotes Tumorigenesis." The Journal of Experimental Medicine, vol. 212, no. 1, 2015, pp. 37-52.
Kulic I, Robertson G, Chang L, et al. Loss of the Notch effector RBPJ promotes tumorigenesis. J Exp Med. 2015;212(1):37-52.
Kulic, I., Robertson, G., Chang, L., Baker, J. H., Lockwood, W. W., Mok, W., Fuller, M., Fournier, M., Wong, N., Chou, V., Robinson, M. D., Chun, H. J., Gilks, B., Kempkes, B., Thomson, T. A., Hirst, M., Minchinton, A. I., Lam, W. L., Jones, S., ... Karsan, A. (2015). Loss of the Notch effector RBPJ promotes tumorigenesis. The Journal of Experimental Medicine, 212(1), 37-52. https://doi.org/10.1084/jem.20121192
Kulic I, et al. Loss of the Notch Effector RBPJ Promotes Tumorigenesis. J Exp Med. 2015 Jan 12;212(1):37-52. PubMed PMID: 25512468.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of the Notch effector RBPJ promotes tumorigenesis. AU - Kulic,Iva, AU - Robertson,Gordon, AU - Chang,Linda, AU - Baker,Jennifer H E, AU - Lockwood,William W, AU - Mok,Winnie, AU - Fuller,Megan, AU - Fournier,Michèle, AU - Wong,Nelson, AU - Chou,Vennie, AU - Robinson,Mark D, AU - Chun,Hye-Jung, AU - Gilks,Blake, AU - Kempkes,Bettina, AU - Thomson,Thomas A, AU - Hirst,Martin, AU - Minchinton,Andrew I, AU - Lam,Wan L, AU - Jones,Steven, AU - Marra,Marco, AU - Karsan,Aly, Y1 - 2014/12/15/ PY - 2014/12/17/entrez PY - 2014/12/17/pubmed PY - 2015/4/22/medline SP - 37 EP - 52 JF - The Journal of experimental medicine JO - J. Exp. Med. VL - 212 IS - 1 N2 - 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. SN - 1540-9538 UR - https://www.unboundmedicine.com/medline/citation/25512468/Loss_of_the_Notch_effector_RBPJ_promotes_tumorigenesis_ L2 - https://rupress.org/jem/article-lookup/doi/10.1084/jem.20121192 DB - PRIME DP - Unbound Medicine ER -