Loss of the Notch effector RBPJ promotes tumorigenesis

Transcriptional regulation by Notch is dependent on interaction with the transcriptional repressor, RBPJ. We show that RBPJ is frequently deleted in human tumors. Depletion of RBPJ in human tumor xenografts was associated with activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced apoptosis. Genome-wide analysis of promoters potentially activated by RBPJ depletion, defined by acetylated histone H4 (H4ac), identified altered H4ac in cell death pathway gene promoters in RBPJ-depleted tumors. Analysis of ChIP-seq data identified several transcription factors that potentially drive expression in RBPJ-depleted cells. Functional studies revealed the contribution of nuclear factor-kB and MYC to increased cell survival. Thus loss of RBPJ derepresses target gene promoters, allowing activation by alternate transcription factors that promote tumorigenesis.