BET bromodomain proteins are required for glioblastoma cell proliferation.
Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Chiara
C
Pastori
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Mark
M
Daniel
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Clara
C
Penas
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Claude-Henry
CH
Volmar
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Andrea L
AL
Johnstone
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Shaun P
SP
Brothers
Department of Neurosurgery; University of Miami Miller School of Medicine; Miami, FL USA.
Regina M
RM
Graham
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Bryce
B
Allen
Department of Radiation Oncology; Mayo Clinic; Rochester, MN USA.
Jann N
JN
Sarkaria
Department of Neurosurgery; University of Miami Miller School of Medicine; Miami, FL USA.
Ricardo J
RJ
Komotar
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Claes
C
Wahlestedt
Center For Therapeutic Innovation; Department of Psychiatry and Behavioral Sciences; University of Miami Miller School of Medicine; Miami, FL USA.
Nagi G
NG
Ayad
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C568713:GSK1210151A
bromodomain; epigenetics; glioblastoma; histone acetylation mimics; histones; stem cells; temozolomide