Abstract
Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Apoptosis
-
Azepines / pharmacology
-
Biomarkers, Tumor / genetics
-
Biomarkers, Tumor / metabolism
-
Blotting, Western
-
Cell Cycle
-
Cell Cycle Proteins
-
Cell Proliferation*
-
Cerebellar Neoplasms / genetics
-
Cerebellar Neoplasms / mortality
-
Cerebellar Neoplasms / pathology
-
Cerebellar Neoplasms / prevention & control*
-
Child
-
Gene Expression Profiling
-
Humans
-
Medulloblastoma / genetics
-
Medulloblastoma / mortality
-
Medulloblastoma / pathology
-
Medulloblastoma / prevention & control*
-
Mice
-
Mice, Nude
-
Neoplastic Stem Cells / drug effects
-
Neoplastic Stem Cells / metabolism
-
Neoplastic Stem Cells / pathology*
-
Nuclear Proteins / antagonists & inhibitors*
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism
-
Oligonucleotide Array Sequence Analysis
-
Prognosis
-
Proto-Oncogene Proteins c-myc / antagonists & inhibitors
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / metabolism*
-
RNA, Messenger / genetics
-
Real-Time Polymerase Chain Reaction
-
Reverse Transcriptase Polymerase Chain Reaction
-
Survival Rate
-
Transcription Factors / antagonists & inhibitors*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism
-
Triazoles / pharmacology
-
Tumor Cells, Cultured
-
Xenograft Model Antitumor Assays
Substances
-
(+)-JQ1 compound
-
Azepines
-
BRD4 protein, human
-
Biomarkers, Tumor
-
Cell Cycle Proteins
-
Nuclear Proteins
-
Proto-Oncogene Proteins c-myc
-
RNA, Messenger
-
Transcription Factors
-
Triazoles