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J Exp Med. 2015 Jan 12;212(1):37-52. doi: 10.1084/jem.20121192. Epub 2014 Dec 15.

Loss of the Notch effector RBPJ promotes tumorigenesis.

Author information

1
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.
2
Genome Sciences Centre, Integrative Oncology Department, and Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
3
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.
4
Experimental Medicine Program and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, British Columbia, Canada.
5
Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany.
6
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.

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.

PMID:
25512468
PMCID:
PMC4291530
DOI:
10.1084/jem.20121192
[Indexed for MEDLINE]
Free PMC Article

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