Journal article
RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation
The Journal of clinical investigation, Vol.126(7), pp.2757-2772
07/01/2016
DOI: 10.1172/JCI86114
PMCID: PMC4922685
PMID: 27322055
Abstract
Glioblastomas co-opt 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. Recombining binding protein suppressor of hairless (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 sternness 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 bromodomain and extraterminal domain (BET) family bromodomain inhibitor decreased MYC and RBPJ expression. Proteomic studies demonstrated that RBPJ binds CDK9, a component of positive transcription elongation factor b (P-TEFb), 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.
Details
- Title: Subtitle
- RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation
- Creators
- Qi Xie - Case Western Reserve UniversityQiulian Wu - Case Western Reserve UniversityLeo Kim - Case Western Reserve UniversityTyler E. Miller - Cleveland Clinic Lerner College of MedicineBrian B. Liau - Center for Systems BiologyStephen C. Mack - Case Western Reserve UniversityKailin Yang - Cleveland Clinic Lerner College of MedicineDaniel C. Factor - Case Western Reserve UniversityXiaoguang Fang - Case Western Reserve UniversityZhi Huang - Case Western Reserve UniversityWenchao Zhou - Case Western Reserve UniversityKareem Alazem - Case Western Reserve UniversityXiuxing Wang - Case Western Reserve UniversityBradley E. Bernstein - Center for Systems BiologyShideng Bao - Cleveland Clinic Lerner College of MedicineJeremy N. Rich - Cleveland Clinic Lerner College of Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.126(7), pp.2757-2772
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI86114
- PMID
- 27322055
- PMCID
- PMC4922685
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 16
- Grant note
- James S. McDonnell Foundation R01CA171652 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Research Programs Committees of Cleveland Clinic Howard Hughes Medical Institute CA197718; CA154130; CA171652; CA169117; CA198892; NS087913; NS089272; NS070315; HG006991 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32GM007250 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01NS089272 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) U54HG006991 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
- Language
- English
- Date published
- 07/01/2016
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696564002771
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