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RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation

Qi Xie, Qiulian Wu, Leo Kim

    The Journal of Clinical Investigation
    |June 21, 2016
    PubMed

    Insights

    Targeting RBPJ, a key regulator of brain tumor-initiating cells (BTICs), shows promise over NOTCH inhibitors. RBPJ controls BTIC stemness and growth by linking MYC and CDK9, offering new therapeutic strategies.

    Area of Science:

    • Neuro-oncology
    • Cancer Stem Cell Biology
    • Molecular Therapeutics

    Background:

    • Glioblastomas (GBMs) utilize stem cell pathways to maintain brain tumor-initiating cells (BTICs).
    • NOTCH signaling is a target in BTICs, but NOTCH antagonists have shown limited clinical efficacy.
    • Recombining binding protein suppressor of hairless (RBPJ) is a central mediator of NOTCH activity.

    Purpose of the Study:

    • To investigate the efficacy of targeting RBPJ compared to NOTCH inhibitors in glioblastoma.
    • To elucidate the role of RBPJ in BTIC self-renewal, stemness, and tumor growth.
    • To identify novel therapeutic vulnerabilities in glioblastoma by understanding RBPJ's regulatory network.

    Main Methods:

    • Pharmacologic NOTCH inhibitors and RBPJ inhibition were compared for tumor growth suppression.
    • Gene expression profiling was used to analyze genes regulated by RBPJ.
    • MYC's interaction with the RBPJ promoter and the effect of BET inhibitors were studied.
    • Proteomic analysis identified RBPJ's interaction with CDK9 and its role in transcriptional elongation.

    Main Results:

    • Targeting RBPJ was more effective in suppressing glioblastoma growth than NOTCH inhibitors.
    • RBPJ regulated distinct genes crucial for BTIC stemness and cell cycle, independent of canonical NOTCH targets.
    • RBPJ is preferentially expressed by BTICs and essential for their self-renewal and tumor propagation.
    • MYC regulates RBPJ expression, and BET inhibitors reduce both MYC and RBPJ levels.
    • RBPJ interacts with CDK9 to enhance transcriptional elongation at target gene promoters.

    Conclusions:

    • RBPJ is a critical regulator of glioblastoma stemness and growth, distinct from canonical NOTCH pathway effects.
    • RBPJ acts as a crucial link between MYC and transcriptional control via CDK9.
    • Targeting RBPJ or its associated pathways presents a promising therapeutic strategy for glioblastoma, potentially overcoming limitations of NOTCH inhibition.

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