BET bromodomain proteins are required for glioblastoma cell proliferation
Language: 
English
Abstract: 

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.

Author(s): 
Pastori, Chiara
Daniel, Mark
Penas, Clara
Volmar, Claude-Henry
Johnstone, Andrea L.
Brothers, Shaun P.
Graham, Regina M.
Allen, Bryce
Sarkaria, Jann N.
Komotar, Ricardo J.
Wahlestedt, Claes
Ayad, Nagi G.
Item Type: 
Journal Article
Publication Title: 
Epigenetics
Journal Abbreviation: 
Epigenetics
Publication Date: 
2014-04
Publication Year: 
2014
Pages: 
611-620
Volume: 
9
Issue: 
4
ISSN: 
1559-2308
DOI: 
10.4161/epi.27906
Library Catalog: 
PubMed
Extra: 
PMID: 24496381 PMCID: PMC4121371

Turabian/Chicago Citation

Chiara Pastori, Mark Daniel, Clara Penas, Claude-Henry Volmar, Andrea L. Johnstone, Shaun P. Brothers, Regina M. Graham, Bryce Allen, Jann N. Sarkaria, Ricardo J. Komotar, Claes Wahlestedt and Nagi G. Ayad. 2014-04. "BET bromodomain proteins are required for glioblastoma cell proliferation." Epigenetics 9: 4: 611-620. 10.4161/epi.27906.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.4161/epi.27906 | issn = 1559-2308 | volume = 9 | pages = 611-620 | last = Pastori | first = Chiara | coauthors = Daniel, Mark, Penas, Clara, Volmar, Claude-Henry, Johnstone, Andrea L., Brothers, Shaun P., Graham, Regina M., Allen, Bryce, Sarkaria, Jann N., Komotar, Ricardo J., Wahlestedt, Claes, Ayad, Nagi G. | title = BET bromodomain proteins are required for glioblastoma cell proliferation | journal = Epigenetics | date = 2014-04 | pmid = | pmc = }} </ref>