BRD4: Epigenetic Regulator and Emerging Cancer Target

The BET family of bromodomain proteins are characterized by the presence of two bromodomains and an ET domain^2,6. 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 domain^2,6; (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 II^2,6>; 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 p53^2,4,6-8.

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 cycle^1-5. In particular, many hematopoietic cancers depend on constant BRD4 activity for expression of Myc^2,3,5,7. 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 carcinomas^2,7. 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 histones^2,3.This effect prevents transcription of Myc and other critical regulatory genes leading to cell cycle arrest^2,3,5. Specific BET inhibitors are currently under development which will allow more selective inhibition of BRD4 and other BET family members^1,3,5,7. 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 resistance^5,7.

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.