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- Title
RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation.
- Authors
Qi Xie; Qiulian Wu; Kim, Leo; Miller, Tyler E.; Liau, Brian B.; Mack, Stephen C.; Kailin Yang; Factor, Daniel C.; Xiaoguang Fang; Zhi Huang; Wenchao Zhou; Alazem, Kareem; Xiuxing Wang; Bernstein, Bradley E.; Shideng Bao; Rich, Jeremy N.; Xie, Qi; Wu, Qiulian; Yang, Kailin; Fang, Xiaoguang
- 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 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 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.
- Subjects
GLIOBLASTOMA multiforme; STEM cell culture; BRAIN tumors; NOTCH genes; CANCER stem cells; PROTEIN metabolism; ANIMAL experimentation; ANIMALS; CELL division; CELL physiology; CELL receptors; CELLULAR signal transduction; EPITHELIAL cells; GENES; GLIOMAS; MICE; PROGNOSIS; RESEARCH funding; STEM cells; PROTEOMICS; SEQUENCE analysis
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 7, p2757
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI86114