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INNOSC Theranostics and
Pharmacological Sciences Enhancers and SEs in cancer treatment

chromatin, is altered in solid tumors. H2A.Z, a highly with typical enhancers. It allows for the rapid formation
conserved histone variant with 60% identity with H2A, is of a highly concentrated and dynamic environment that
related to transcriptional activation. In mammals, there promotes effective transcription. 48,49 Growing data from
are two paralogues of H2A.Z: H2A.Z.1 and H2A.Z.2. Their in vitro and in vivo studies strongly support the notion
expression is typically upregulated in numerous tumor types. that phase separation may be employed to elucidate
MYC, ERα, and AR TFs can drive the addition of H2A.Z.1 the characteristics of SEs, encompassing their function,
to genomic sites in hormone-regulated malignancies such development, and susceptibility. Nevertheless, this model
as breast and prostate cancer. Furthermore, SEs activate attempts to elucidate the precise order of events involved in
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the histone chaperone HJURP, resulting in abnormally the development of long-distance chromatin connections
high HJURP expression in t(4;14)-positive multiple or the generation of transcriptional condensates. Research
myeloma. Overexpression of HJURP enhances tumor cell has demonstrated that the levels and alterations of RNA
proliferation and is linked to poor outcomes in t(4;14)- molecules have a regulatory impact on the creation and
positive multiple myeloma patients. Enhancer hijacking dissolution of condensates. Condensate production is
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may potentially increase resistance to treatment, rendering facilitated by synergistic interactions among polyvalent
SEs more vulnerable to epigenetic therapies than canonical molecules, such as RNA, DNA, and intrinsically disordered
enhancers. This is because SEs arise when master TFs regions (IDRs) in proteins. 50
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attach to each component enhancer, attracting unusually Plenty of evidence indicates that SEs undergo sudden
high densities of cofactors (mediators and coactivators) modifications in formation and dissolution. They arise by
that are proposed to interact with enhancers.
a single nucleation event and disassemble when chromatin
However, not all cofactors are essential for SEs factors or nucleation regions are removed. These features
activation. In HCT116 cells, enhancers have been classified were observed in murine embryonic stem cells. The
based on their cofactor dependencies, highlighting disruption of MED1 and BRD4 by 1,6-hexanediol leads
different mechanisms for activating their correlated SEs to the formation of distinct structures at specific enhancer
and, thus, transcription. This framework of categorization elements within the cell nuclei. This disruption also led to
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permits us to comprehend how enhancers contribute to the excision of MED1 and BRD4 from the chromatin at
gene expression programs and regulatory specificity. enhancers, as well as the loss of RNA pol II. RNA pol II
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Furthermore, the amount of mediators is elevated selectively accessed the mediator condensates through the
compared to other regions, making it a useful indicator IDR located at the phosphorylated C-terminal domain of
for identifying SEs. Therefore, the transcription-activated the large subunit. RNA-binding proteins located near the
complexes recruited by SEs display about 10-fold their promoter of downstream stemness genes, such as TP63,
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molecular density of conventional enhancers. These MET, and FOSL1, recruit RNA pol II to activate cancer
complexes require a stable structure to preserve their stemness features in squamous cell carcinoma (Figure 2).
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conformation in optimal conditions. High-mobility group The administration of bromodomain and extra-terminal
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proteins, such as HMGA1, are necessary for preserving the domain (BET) inhibitors effectively disrupted SEs,
enhancer substructures of coactivators such as mediator resulting in a strong inhibition of cancer stem cells (CSCs)
subunit 1 (MED1) and bromodomain-containing protein self-renewal and the complete eradication of CSCs in a
4 (BRD4). BRD4 functions as an epigenetic reader that mouse model of human head-and-neck squamous cell
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targets and interacts with acetylated lysine residues on carcinoma (HNSCC). Furthermore, the disruption of SEs
histone H3 and H4. When BRD4 binds to these residues, it also hinders the spread and migration of CSCs derived
recruits the mediator complex, RNA pol II, and the positive from human HNSCC to the lymph nodes. Nevertheless,
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transcription elongation factor b, facilitating the process of the use of anti-BRD4 agonists as a therapeutic option
transcription initiation and elongation. 44,45 remains restricted due to their high toxicity and delivery
The high levels of RNA pol II and cofactors in limitations. As a result, new methods combining genomic
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SEs create a condensate by establishing multivalent and computational frameworks have been developed
interactions, resulting in the formation of liquid droplets. to identify BRD4-enriched SEs and confirm their
This phenomenon may be explained by a model based on involvement in promoting the growth and movement of
the process of liquid-liquid phase separation. The model, cancer cells through CRISPR knockouts. 40,54 Within this
proposed by Hnisz et al., 46,47 suggests that the dense perspective, drug design can be accomplished through a
concentration of TFs, RNA pol II, cofactors, and eRNAs physicochemical mechanism of action, which offers a new
enables the formation of localized phase separation through method to target cellular components that were previously
weak multivalent interactions among molecules associated considered difficult to drug, such as intrinsically disordered
with SEs. This process would be more difficult to achieve proteins. 47,55

Volume 7 Issue 3 (2024) 4 doi: 10.36922/itps.3654