BRD4: Epigenetic Regulator and Emerging Cancer Target
The BET family of bromodomain proteins are characterized by the presence of two bromodomains and an ET domain2,6. Of these, BRD4 is the most well-studied. BRD4 has four primary molecular functions. It (i) maintains chromatin structure via binding acetylated histones, an activity mediated by sites in the N-terminal domain; (ii) Histone Acetyl Transferase (HAT) activity via its HAT catalytic domain2,6; (iii) serine kinase activity via a kinase domain that spans the N-terminal region and phosphorylates residues in the C-terminal domain of RNA Pol II2,6>; and (iv) the C-terminal domain serves as a binding and nucleation site for transcription factors and complexes. BRD4 is found in several transcription complexes, including the general cofactor Mediator and the P-TEFb elongation factor6. The C terminal domain also mediates the interactions of BRD4 with many well-known transcriptional regulators, most notably P-TEFb, MYC, NFκb, and p532,4,6-8.
BRD4 has recently come to light as a possible target for cancer therapy because of its role as a transcriptional and epigenetic regulator of the cell cycle1-5. In particular, many hematopoietic cancers depend on constant BRD4 activity for expression of Myc2,3,5,7. Solid tumors are also associated with BRD4 activity2. Deregulation of BRD4 is clinically linked to breast, colon, and prostate cancers7. Interestingly, a BRD4 fusion protein, BRD4-NUT, is found in aggressive midline carcinomas2,7. Whether BRD4 plays a further role in metastasis is unclear2.
To date, most available BET inhibitors affect all BET family members producing unpredictable and sometimes dangerous results1. BET inhibitors work by blocking the association of BRD4 with chromatin by mimicking acetyl-lysine residues on histones2,3.This effect prevents transcription of Myc and other critical regulatory genes leading to cell cycle arrest2,3,5. Specific BET inhibitors are currently under development which will allow more selective inhibition of BRD4 and other BET family members1,3,5,7. BET inhibitors may be especially effective in combination with a variety of other chemotherapeutic agents by enabling the use of lower doses of toxic drugs and by helping to overcome resistance5,7.
Recognizing its importance in cell cycle regulation and tumorigenesis, Bethyl manufactures rigorously tested antibodies to BRD4 and many other related proteins to promote the advancement of cancer research.