RBPJ maintains brain tumor–initiating cells through CDK9-mediated transcriptional elongation
Qi Xie, Qiulian Wu, Leo Kim, Tyler E. Miller, Brian B. Liau, Stephen C. Mack, Kailin Yang, Daniel C. Factor, Xiaoguang Fang, Zhi Huang, Wenchao Zhou, Kareem Alazem, Xiuxing Wang, Bradley E. Bernstein, Shideng Bao, Jeremy N. Rich
Qi Xie, Qiulian Wu, Leo Kim, Tyler E. Miller, Brian B. Liau, Stephen C. Mack, Kailin Yang, Daniel C. Factor, Xiaoguang Fang, Zhi Huang, Wenchao Zhou, Kareem Alazem, Xiuxing Wang, Bradley E. Bernstein, Shideng Bao, Jeremy N. Rich
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Research Article Oncology

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

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.

Authors

Qi Xie, Qiulian Wu, Leo Kim, Tyler E. Miller, Brian B. Liau, Stephen C. Mack, Kailin Yang, Daniel C. Factor, Xiaoguang Fang, Zhi Huang, Wenchao Zhou, Kareem Alazem, Xiuxing Wang, Bradley E. Bernstein, Shideng Bao, Jeremy N. Rich

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Figure 9

RBPJ and CDK9 regulation informs patient prognosis.

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RBPJ and CDK9 regulation informs patient prognosis. (A and B) Relative m...
(A and B) Relative mRNA expression levels of (A) RBPJ and (B) CDK9 in nontumor brain and glioblastoma were determined in TCGA data set. (C) Analysis of TCGA data indicates that non–G-CIMP glioblastoma (GBM) patients have much poorer survival (P < 0.0001 by log-rank analysis). (D) Analysis of TCGA data indicates that higher RBPJ mRNA expression informs poor prognosis of non–G-CIMP patients (P = 0.0483 by log-rank analysis). (E) Analysis of TCGA data indicates that higher CDK9 mRNA expression informs poor prognosis of non–G-CIMP patients (P = 0.0157 by log-rank analysis). (F) Pairwise correlation analysis of RBPJ and transcriptional elongation–related genes was performed in the TCGA glioblastoma data set. Plots indicate expression data from TCGA patients for indicated genes, and numbers represent correlation coefficient (r) values.