Page 74 - ITPS-7-3

INNOSC Theranostics and
Pharmacological Sciences Enhancers and SEs in cancer treatment

discovered that a significant portion of enhancers and SEs can affect the interaction among transcription regulatory
can be transcribed to give rise to eRNAs/SE RNAs that can elements (enhancer, promoter, and TFs binding site).
further facilitate enhancer-promoter interactions, RNA Such genetic variations or epigenetic modifications often
pol II elongation, and can even act as decoys for repressive result in loop formation between proto-oncogenes and
cofactors. 15-18 enhancers, leading to the upregulation of neighboring
oncogenes and tumorigenesis. For example, a single
2. Oncogenic enhancer and SEs activation nucleotide polymorphism (SNP) within the 15q15.1 chronic
by genomic rearrangements and variations lymphocytic leukemia risk locus can create SEs that are
Chromosomal rearrangements, such as deletions, correlated with decreased proapoptotic BMF expression.
inversions, duplications, or translocations, can misplace This SNP also hinders the interaction between the TF
active enhancers within the genome, causing abnormal RELA (p65) and SE, resulting in an enhancement of BCL2’s
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gene expression. Such chromosomal rearrangements antiapoptotic function, thereby facilitating tumor growth.
can lead to the activation of oncogenes or the silencing In addition, chromosomes are folded and arranged into
of tumor suppressor genes, commonly associated with 3D genomic segments that are megabases in length and
cancer development. 19-22 Recent findings suggest that have the ability to self-interact. However, interactions with
genomic rearrangements can lead to the repositioning of regions beyond the designated topologically associated
distal enhancers to the promoters of oncogenes specific domains (TADs) are infrequent. Interactions of enhancers
to certain tumor types. These enhancers, which were not with their target genes are constrained due to the TAD
originally intended for these oncogenes, contribute to the boundaries enriched with insulator proteins such as CTCF
initiation and progression of tumorigenesis by activating in mammalian cells. 26,27 TAD boundary disruption due to
oncogenic signals. This phenomenon, known as enhancer chromosomal rearrangements or mutations can result in
hijacking, is a crucial cancer-driver mechanism. enhancers interacting with genes outside of the original TAD,
For instance, enhancers specific to the lymphoma resulting in inappropriate enhancer-promoter interactions.
subtype within the MYC locus were shown to be silenced in Such interactions have been implicated in rare diseases
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lymphomas and associated with germline polymorphisms such as adult-onset demyelinating leukodystrophy, and
29,30
that alter the risk of developing lymphoma. Additionally, human limb malformation.
enhancers within the BCL6 locus are subject to acetylation A few studies have investigated TAD boundary
and possess the capability to undergo genomic duplication. disruption in carcinogenesis. 31,32 Interestingly, mutations in
Moreover, they can activate the MYC promoter, thereby the CTCF motif at the TAD boundary result in NOTCH1
functioning as an enhancer donor in a translocation misregulation associated with ovarian cancer, due to the
phenomenon referred to as enhancer hijacking (Figure 1). 23 aberrant activity of enhancers caused by the disruption of
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In another study, Gröschel et al. demonstrated that the TAD. However, more studies are required to unravel
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chromosomal 3q rearrangements result in the relocation TAD boundary disruptions and their connection to cancer
of a distal GATA2 enhancer (located 110 kb away from the initiation and development.
GATA2 gene at 3q21) to the EVI1 locus. This event leads 3. Influence of SEs on tumor
to the ectopic activation of EVI1 expression, which is a microenvironment
crucial oncogenic driver in acute myeloid leukemia (AML).
Furthermore, the elimination of the ectopic EVI1 enhancer Cancer cells exhibit modified patterns of SE regulations,
using the CRISPR/Cas9 genome-editing system resulted in which contribute to the activation of oncogenes and other
decreased cell proliferation and increased apoptosis in the genes associated with key cancer features. 34,35 Chromosomal
MUTZ-3 cell line derived from myeloid leukemia. These translocations in malignant lymphomas can relocate SEs to
effects were remarkably similar to those observed when immunoglobulin loci near MYC, resulting in elevated levels
EVI1 knockdown was achieved using small hairpin RNA of MYC expression. Mechanistically, MYC overexpression
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in the same cells. may be reciprocally related to hijacking histone deposition,
These findings propose that chromosomal which alters cancer genome organization, as observed in
rearrangements can lead to the repositioning of a single the U2OS osteosarcoma cell line. Immunofluorescence
enhancer, consequently impacting the regulation of two labeling demonstrated that MYC molecules formed
distinct distal genes, ultimately contributing to cancer punctate foci at active transcriptional SEs, which were
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development. In addition to chromosomal rearrangements, abrogated on removal of the architectural protein CTCF.
genetic variations such as deletions, mutations, or epigenetic Hijacking histone variants and chaperones, which
modulations, such as methylation at the enhancer site, transport histones across the cell and deposit them in

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