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Global Translational Medicine Critical roles for BRD4 identified in cancer

Table 1. Examples of BET inhibitors Y97/98 promotes interaction with STAT3 in the tumor
microenvironment and promotes the transcriptional
BET inhibitors Functions program through chromatin remodeling and activation
JQ1 Inhibition of tumor cell proliferation and of carcinogenic enhancers, such as MYC, CXCL1, and
promotion of tumor cell apoptosis are CXCL2. This study provides insights into a more effective
achieved through JQ1 suppressing the
target genes of BRD4 [63,77] . cancer treatment that emphasized on the inhibition of IL6/
Molibresib (GSK525762) GSK525762 has antitumor activity in IL8-JAK2 signaling to reduce phosphorylation of BRD4
preclinical models of carcinoma and non- and sensitize the cancer cells to BET inhibitors.
small cell lung cancer [78,79] .
OTX-015 (MK-8628) NSCLC cell lines translocated with or 8. BET inhibitors
without EML4-ALK undergo reduced The BET inhibitor prevents protein-protein interactions
proliferation and are arrested in the cell between acetylated histones and transcription factors by
cycle when treated with OTX015 .
[80]
I-BET151(GSK1210151A) BET151 inhibits BET selectively and binding reversibly to the bromodomains of the BRD2 and
. Some noteworthy BET inhibitors are
BRD3 proteins
[25,76]
functions similarly to temozolomide.
I-BET151 decreases cell percentage in listed in Table 1.
S/G2 phase and increases cell apoptosis in
a dose-dependent manner in six myeloma 9. Conclusion
cell lines . BRD4 and BET family members are epigenetic readers,
[78]
BI894999 BRD-NUT is rapidly dislodged writers, and erasers, which are implicated in cancer
from chromatin following BI894999
treatment . development. BRD4 and its BET family protein play
[81]
essential roles in DNA damage repair, NFκB signaling,
BET: Bromodomain and extra-terminal
interaction with c-Myc, and transcription regulation
of essential in cancers, as well as link transcription at
enhancers and genes to regulate enhancer transcription.
In addition, post-translational modifications also play
critical roles in BRD4-mediated tumorigenesis (Figure 5).
Colocalization of BRD4 to enhancer and promoter-
proximal gene regions enables elongation activation at
enhancer genes. As BRD4 inactivation could inhibit cancer
development, BRD4 is now recognized as a promising
therapeutic target. Meanwhile, by regulating tumor-related
gene expressions, post-translational modification functions
of BRD4 contribute to the development of tumors. Apart
from that, BRD4 inhibition induces chromatin remodeling
and leads to the regulation of oncogenes responsible
for tumor progression. To address the BRD4-mediated
Figure 5. A summary of bromodomain-containing protein 4 (BRD4) carcinogenesis, small-molecule inhibitors targeting
functions. BRD4 is involved in DNA repair, transcriptional regulation, functional domains of BRD4 and BET family proteins are
and post-translational modifications, as well as regulation of cancer currently under investigation.
progression.
Acknowledgments
inhibitor resistance and tumor development has been None.
mechanistically deciphered.
Funding
7.2. Phosphorylation
None.
It has been demonstrated that phosphorylating BRD4
at the tyrosine 97/98 (Y97/98) site could improve the Conflict of interest
binding of BRD4 to chromatin but decrease binding to
BET inhibitor, which gives rise to BET inhibitor resistance. The author declares no conflicts of interest.
BRD4 is phosphorylated at Y97/98 by the matrix signal Author contributions
IL-6/8 (IL-6/8-JAK2) in colorectal cancer . Further
[75]
experiments showed that BRD4 phosphorylation at This is a single-authored paper.

Volume 2 Issue 3 (2023) 7 https://doi.org/10.36922/gtm.1442