BET

Overview

The bromodomain and extraterminal (BET) proteins are a bromodomain subfamily that includes BRD2, BRD3, BRD4, and BRDT.1

  • Characterized by the presence of two acetyl-histone reading bromodomains and an ET domain2-4

The BET proteins utilize bromodomains to interact with acetylated histone tails and mediate downstream functions, such as histone acetylation recognition, chromatin remodeling, and transcription regulation.1,5

  • Bind to acetylated chromatin and target chromatin-modifying enzymes to specific sites6
  • Activate transcription of genes, especially of those associated with the cell-cycle4

Implications in cancer

BET family proteins are involved in promoting aberrant oncogene expression in a variety of cancers.7-10

Overexpression and gain-of-function mutations of BET proteins can alter gene transcription, histone modification, DNA repair, and apoptosis.1

BRD4 is implicated in a number of hematological and solid tumors.11

  • Modulates transcription elongation of essential genes involved in cell cycle and apoptosis, such as c-Myc and BCL-2.

Oncogenic Expression

Acute Myeloid Leukemia

  • The BET family of proteins may be involved in the pathogenesis of AML, particularly in AML harboring mutations in NPM1 and MLL.12
    • Dysregulated transcription causes overexpression of critical oncogenes, including c-Myc and BCL-2.12,13
  • Additionally, the BET family of proteins likely promotes oncogenesis through a number of shared pathways activated in FLT3 AML, including STAT5, AKT, and ERK.9,12
  1. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16(4):241-263.
  2. Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513(1):124-128.
  3. Wadhwa E, Nicolaides T. Bromodomain inhibitor review: bromodomain and extra-terminal family protein inhibitors as a potential new therapy in central nervous system tumors. Cureus. 2016;8(5):e620.
  4. Garcia-Gutierrez P, Mundi M, Garcia-Dominguez M. Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B. J Cell Sci. 2012;125(Pt 15):3671-3680.
  5. Wu SY, Chiang CM. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem. 2007;282(18):13141-13145.
  6. Muller S, Filippakopoulos P, Knapp S. Bromodomains as therapeutic targets. Expert Rev Mol Med. 2011;13:e29.
  7. Fu LL, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6(8):5501-5516.
  8. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
  9. Liu S, Walker SR, Nelson EA, et al. Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2. Mol Cancer Ther. 2014;13(5):1194-1205.
  10. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669-16674.
  11. Jung M, Gelato KA, Fernández-Montalván A, Siegel S, Haendler B. Targeting BET bromodomains for cancer treatment. Epigenomics. 2015;7(3):487-501.
  12. Abedin SM, et al. BET inhibitors in the treatment of hematologic malignancies: current insights and future prospects. Onco Targets Ther. 2016;9:5943-5953.
  13. Dawson MA, Gudgin EJ, Horton SJ, et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014;28(2):311-320.

Need more information?

Explore Careers

Contact Medical Information

For All Other Information