|
| Status |
Public on May 01, 2016 |
| Title |
RNA-seq Profiles in RBPJ Maintains Brain Tumor Initiating Cells through CDK9-mediated Transcriptional Elongation |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Glioblastomas coopt stem cell regulatory pathways to maintain brain tumor initiating cells (BTICs), also known as cancer stem cells. Notch signaling has been a molecular target in BTICs, but Notch antagonists have demonstrated limited efficacy in clinical trials. RBPJ is considered a central transcriptional mediator of Notch activity. Here, we report that pharmacologic Notch inhibitors were less effective than targeting RBPJ in suppressing tumor growth. While Notch inhibitors decreased canonical Notch gene expression, RBPJ regulated a distinct profile of genes critical to BTIC stemness and cell cycle progression. RBPJ was preferentially expressed by BTICs and required for BTIC self-renewal and tumor growth. MYC, a key BTIC regulator, bound the RBPJ promoter and treatment with a BET family bromodomain inhibitor decreased MYC and RBPJ expression. Proteomic studies demonstrated that RBPJ binds CDK9, a component of P-TEFb (positive transcription elongation factor), to target gene promoters, enhancing transcriptional elongation. Collectively, RBPJ links MYC and transcriptional control through CDK9, providing potential nodes of fragility for therapeutic intervention, potentially distinct from Notch.
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| |
|
| Overall design |
RNA-seq of primary patient-derived GBM brain tumor initiating cells with DAPT treatment or shRBPJ treatment
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| |
|
| Contributor(s) |
Xie Q, Miller TE, Liau BB, Bernstein BE, Rich JN |
| Citation(s) |
27322055 |
| |
| Submission date |
Mar 30, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Tyler E Miller |
| Organization name |
Cleveland Clinic Lerner Research Institute
|
| Department |
Stem Cell Biology and Regenerative Medicine
|
| Lab |
Jeremy Rich Lab
|
| Street address |
2111 E 96th Street, NE3-256
|
| City |
Cleveland |
| State/province |
Ohio |
| ZIP/Postal code |
44106 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (12)
|
|
| This SubSeries is part of SuperSeries: |
| GSE79736 |
RBPJ Maintains Brain Tumor Initiating Cells through CDK9-mediated Transcriptional Elongation |
|
| Relations |
| BioProject |
PRJNA316861 |
| SRA |
SRP072573 |
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