RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation.
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.
Qi
Q
Xie
Qiulian
Q
Wu
Leo
L
Kim
Tyler E
TE
Miller
Brian B
BB
Liau
Stephen C
SC
Mack
Kailin
K
Yang
Daniel C
DC
Factor
Xiaoguang
X
Fang
Zhi
Z
Huang
Wenchao
W
Zhou
Kareem
K
Alazem
Xiuxing
X
Wang
Bradley E
BE
Bernstein
Shideng
S
Bao
Jeremy N
JN
Rich
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D002455:Cell Division; D049109:Cell Proliferation; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000072417:Protein Domains; D040901:Proteomics / Q000379:methods; D051880:Receptors, Notch / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; C467969:CDK9 protein, human; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9