Loss of the Notch effector RBPJ promotes tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Aberrant Notch signaling contributes to oncogenesis in various cancers.
• The role of downstream Notch pathway elements in tumor growth remains incompletely understood.
• Transcriptional regulation by Notch involves the repressor RBPJ, which modulates gene promoter activity.

Purpose of the Study:

• To investigate the impact of RBPJ depletion on tumor growth and gene expression.
• To identify the mechanisms by which RBPJ loss influences cancer cell survival and tumorigenesis.
• To explore the role of epigenetic modifications and alternative transcription factors in RBPJ-deficient tumors.

Main Methods:

• Analysis of RBPJ depletion in human cancer cell lines xenografted into immunodeficient mice.
• Global profiling of histone H4 acetylation (H4ac) to identify activated genomic regions.
• Transcription factor binding analysis and functional studies involving NF-κB and MYC.

Main Results:

• RBPJ is frequently depleted in human tumors.
• RBPJ depletion activates canonical Notch target genes and accelerates tumor growth by reducing cell death.
• Epigenetic dysregulation of the cell death pathway and Notch-independent activation by NF-κB and MYC were observed in RBPJ-depleted tumors.

Conclusions:

• Loss of RBPJ promotes tumorigenesis by derepressing target gene promoters.
• Alternative transcription factors, including NF-κB and MYC, drive cancer cell survival in a Notch-independent manner following RBPJ depletion.
• RBPJ depletion represents a critical event that facilitates tumor progression through altered transcriptional landscapes.