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Global Translational Medicine Critical roles for BRD4 identified in cancer

terminal helices of BRD4 and in the region proximal to and C-terminus, the BRD4 complex can facilitate
its acetyl-lysine docking site . Bromodomains recognize recruitment and interaction with other factors in a bigger
[9]
acetylated histones and other proteins through these two extent . The A motif is critical for its binding to the
[13]
helices, along with the ZA loop (Figure 1). Amino acid C-terminal domain of RNA polymerase II. The C-terminus
substitutions in these regions can alter the specificity of BRD4 binds to c-Myc and inhibits its HAT activity [12,14] .
and affinity of the acetyl-lysine binding pocket, leading Taken together, the distinct enzyme domains of BRD4
to aberrant recruitment of transcriptional regulators contribute to transcriptional regulation by increasing the
and gene expression dysregulation. Several studies have access of transcriptional regulators to chromatin.
identified specific amino acid substitutions in BRD4 that
are associated with oncogenesis. For example, G485D in 3. BRD4 and transcriptional regulation
the αB helix has been shown to increase BRD4 interaction BRD4 has been shown to regulate transcription in both
with acetylated histones and to promote cancer survival. in vivo and in vitro models. The interaction between BRD4
Other substitutions in the αB and αC helices, such as and chromosomes during mitosis could identify the genes
E429V and P593L, have also been shown to promote whose transcription has already begun in G1 phase, which
oncogenic properties in various cancer types . Overall, are required to ensure cell cycle progression [15-18] . Apart
[9]
these findings underscore the importance of BRD4 as a from that, BRD4 also helps to maintain embryonic stem cell
transcriptional regulator in both normal cellular processes characteristics, and it is essential during embryogenesis [19-21]
and carcinogenesis. In view of its dysregulation in cancer, and cell identity determination during both early phases
BRD4 might serve as a prime candidate for therapeutic and development. During early phases of embryogenesis,
targeting, and more detailed studies are required to provide BRD4 regulates the self-renewal and pluripotency
[20]
valuable insights into the molecular mechanisms driving of embryonic stem cells by controlling Nanog and
tumorigenesis. OCT4 . In vivo, BRD4-deficient embryos, which lack
[21]
sufficient BRD4 function, exhibit developmental defects,
2. BRD4 enzymatic activities particularly during the early stages of development, which
[22]
BRD4 has two isoforms. BRD4 long isoform (BRD4-L) is can lead to embryo lethality shortly after implantation .
a protein of 152 kDa that contains BD1 and BD2 domains, The unfavorable outcome can be justified by its inability to
an ET domain, and a C-terminal domain, whereas BRD4 maintain the inner cell mass, which is crucial for proper
short isoform (BRD4-S), originally called HUNK1 , embryo development. BRD4 plays a crucial role in cell
[10]
is approximately 81 kDa and consists of BD1 and BD2 identity determination during development by selectively
domains, an ET domain, and a C-terminal domain regulating lineage-specific genes. During embryonic
(Figure 1). Unless otherwise stated, the BRD4 mentioned development, pluripotent stem cells develop into various
in this review refers to BRD4-L only. differentiated cell types through a process known as
differentiation. This process is tightly controlled by
The enzymatic activities of BRD4 are distinctly transcriptional factors and epigenetic regulators, such as
different from those of other BET family proteins. Kinase BRD4, which help establish and maintain cell identity .
[23]
and histone acetyltransferase (HAT) activity are enzyme In addition to its role in development, dysregulation of
functions intrinsic to BRD4, enabling the dynamic BRD4 activity has been implicated in the progression of
regulation of its interacting partners. Through its kinase various diseases.
activity, BRD4 phosphorylates many of its interacting
BRD4 also serves as a transcriptional activator and a
partners, including c-Myc, TATA-box binding protein histone code reader (Figure 2) . BRD4 is a recognized
[24]
associated factor 7 (TAF7), P-TEFb, and most importantly, as transcription activator, even though it can also act
the C-terminal domain of RNA polymerase II , thereby as a transcriptional repressor [25,26] . In addition, BRD4
[11]
directly controlling their transcription. BRD4 contains accumulates in hyperacetylated and transcriptionally-
an HAT domain, which acetylates histone proteins in the prone chromatin regions where it reads the histone code,
[12]
nucleosome . Following the histone acetylation by BRD4, where it acts as a nucleation center for large protein
the chromatin structure is loosened to enable DNA-histone complexes whose function is to stimulate transcription
interactions, increasing the access of transcription factors initiation and elongation, leading to RNA polymerase II
and regulatory proteins to DNA and then altering the cell activity. Transcription factors transmit signals between
behavior.
enhancers and their target genes . This function largely
[27]
Other domains and motifs in BRD4 assist with the relies on BRD4 with its colocalization with genes and
enzymatic activities or interact with multiple factors in a enhancer regions [28,29] , as well as its BD domains and
positive manner. On structural binding with N-terminus their ability to recognize acetyl proteins [10,11] . Bressin et al.

Volume 2 Issue 3 (2023) 3 https://doi.org/10.36922/gtm.1442