BET bromodomain proteins are required for glioblastoma cell proliferation

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, Nagi G. Ayad

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)611-620
Number of pages10
JournalEpigenetics
Volume9
Issue number4
DOIs
StatePublished - Feb 19 2014

Fingerprint

Glioblastoma
Cell Proliferation
temozolomide
Cell Cycle
Protein Domains
Therapeutics
Nuclear Proteins
Multiple Myeloma
Heterografts
Epigenomics
Brain Neoplasms
Histones
Lysine
GSK1210151A
Testis
Neoplasms
Leukemia
Stem Cells
RNA
Carcinoma

Keywords

  • Bromodomain
  • Epigenetics
  • Glioblastoma
  • Histone acetylation mimics
  • Histones
  • Stem cells
  • Temozolomide

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Medicine(all)

Cite this

Pastori, C., Daniel, M., Penas, C., Volmar, C. H., Johnstone, A. L., Brothers, S. P., ... Ayad, N. G. (2014). BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics, 9(4), 611-620. https://doi.org/10.4161/epi.27906

BET bromodomain proteins are required for glioblastoma cell proliferation. / 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.

In: Epigenetics, Vol. 9, No. 4, 19.02.2014, p. 611-620.

Research output: Contribution to journalArticle

Pastori, C, Daniel, M, Penas, C, Volmar, CH, Johnstone, AL, Brothers, SP, Graham, RM, Allen, B, Sarkaria, JN, Komotar, RJ, Wahlestedt, C & Ayad, NG 2014, 'BET bromodomain proteins are required for glioblastoma cell proliferation', Epigenetics, vol. 9, no. 4, pp. 611-620. https://doi.org/10.4161/epi.27906
Pastori C, Daniel M, Penas C, Volmar CH, Johnstone AL, Brothers SP et al. BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics. 2014 Feb 19;9(4):611-620. https://doi.org/10.4161/epi.27906
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. / BET bromodomain proteins are required for glioblastoma cell proliferation. In: Epigenetics. 2014 ; Vol. 9, No. 4. pp. 611-620.
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