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Enhancer hijacking: Innovative ways of carcinogenesis

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Ruby Dhar
Ruby Dhar
Arun Kumar
Arun Kumar
Arun Kumar
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Subhradip Karmakar at All India Institute of Medical Sciences
Subhradip Karmakar
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Abstract

Enhancer elements are specific DNA sequences that play a crucial role in regulating gene expression. Located upstream or downstream in the genomic context, enhancers enhance the transcription of linked genes. This is achieved by providing binding sites for transcription factors and other proteins, acting as a nucleation point that promotes the assembly of the transcriptional machinery. What makes enhancers unique is that located even thousands of base pairs away, they can exert their function. They can act over long distances, looping to interact with the promoter region of their target genes. Enhancers are often involved in cell type-specific gene expression as different cells express different sets of genes by activating and repressing cell type-specific enhancers. Cancer cells seem to co-opt this mechanism and hijack it for their own survival. In this process, an aberrant enhancer element activates the transcription of oncogenes (genes that have the potential to cause cancer) due to some alterations in genomic structure or regulatory elements that happen in cancer, contributing to tumorigenesis and cancer progression. Enhancer hijacking often occurs through complex genomic rearrangements such as chromosomal translocations and other structural rearrangements such as deletions or amplifications.8 These alterations can bring a usually distant, far-located enhancer into proximity with an oncogene, leading to its inappropriate activation. This is often seen in various cancers, including leukemias and solid tumors. Enhancer hijacking and its effects on gene regulation in cancer are frequently studied using methods such as RNA sequencing, chromatin conformation capture, and CRISPR-Cas9. Finding an enhancer hijacking event may be used to inform treatment choices, especially in precision medicine settings, and may also function as a biomarker for particular cancer types.
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Asian Journal of Medical Sciences | Sep 2024 | Vol 15 | Issue 9 1
Enhancer elements are specific DNA sequences that
play a crucial role in regulating gene expression.1 Located
upstream or downstream in the genomic context, enhancers
enhance the transcription of linked genes.2 This is achieved
by providing binding sites for transcription factors and
other proteins, acting as a nucleation point that promotes
the assembly of the transcriptional machinery.3,4
What makes enhancers unique is that located even
thousands of base pairs away, they can exert their function.
They can act over long distances, looping to interact with
the promoter region of their target genes.5 Enhancers
are often involved in cell type-specic gene expression as
different cells express different sets of genes by activating
and repressing cell type-specic enhancers.6
Cancer cells seem to co-opt this mechanism and hijack
it for their own survival. In this process, an aberrant
enhancer element activates the transcription of oncogenes
(genes that have the potential to cause cancer) due to some
alterations in genomic structure or regulatory elements that
happen in cancer, contributing to tumorigenesis and cancer
progression.7 Enhancer hijacking often occurs through
complex genomic rearrangements such as chromosomal
translocations and other structural rearrangements such as
deletions or amplications.8 These alterations can bring a
usually distant, far-located enhancer into proximity with
an oncogene, leading to its inappropriate activation. This
is often seen in various cancers, including leukemias9 and
solid tumors.9,10
Enhancer hijacking and its effects on gene regulation
in cancer are frequently studied using methods such as
RNA sequencing, chromatin conformation capture, and
CRISPR-Cas9.11,12 Finding an enhancer hijacking event may
be used to inform treatment choices, especially in precision
medicine settings, and may also function as a biomarker
for particular cancer types.
Ruby Dhar1, Arun Kumar2, Subhradip Karmakar3
1Scientist, Room 3020, 3Additional Professor, Department of
Biochemistry, All India Institute of Medical Sciences, New Delhi,
2Professor, Department of Biochemistry, Narayan Medical College,
Gopal Narayan Singh University, Sasaram, Bihar, India
Address for Correspondence:
Dr. Subhradip Karmakar, Additional Professor,
Department of Biochemistry, All India Institute of Medical
Sciences, New Delhi, India. Mobile: +91-9999612564.
E-mail: subhradipaiims@gmail.com
Dr. Arun Kumar, Professor, Department of Biochemistry,
Narayan Medical College, Gopal Narayan Singh University,
Sasaram, Bihar, India. Mobile: +91-7584089886.
E-mail: profdrarunk@gnsu.ac.in
REFERENCES
1. Enhancers. Available from: https://www.nature.com/scitable/
denition/enhancer-163 [Last assessed on 2024 Aug 04].
2. Karnuta JM and Scacheri PC. Enhancers: Bridging the gap
between gene control and human disease. Hum Mol Genet.
2018;27(R2):R219-R227.
https://doi.org/10.1093/hmg/ddy167
3. Kulaeva OI, Nizovtseva EV, Polikanov YS, Ulianov SV and
Studitsky VM. Distant activation of transcription: Mechanisms of
enhancer action. Mol Cell Biol. 2012;32(24):4892-4897.
https://doi.org/10.1128/MCB.01127-12
4. Kyrchanova O and Georgiev P. Mechanisms of enhancer-promoter
interactions in higher eukaryotes. Int J Mol Sci. 2021;22:671.
https://doi.org/10.3390/ijms22020671
5. Panigrahi A and O’Malley B. Mechanisms of enhancer action:
The known and the unknown. Genome Biol. 2021;22(1):108.
https://doi.org/10.1186/s13059-021-02322-1
6. Claringbould A and Zaugg JB. Enhancers in disease: Molecular
basis and emerging treatment strategies. Trends Mol Med.
2021;27(11):1060-1073.
Enhancer hijacking: Innovative ways of
carcinogenesis
EDITORIALS ASIAN JOURNAL OF MEDICAL SCIENCES
Submission: 05-08-2024 Revision: 15-08-2024 Publication: 01-09-2024
Access this article online
Website:
http://nepjol.info/index.php/AJMS
DOI: 10.3126/ajms.v15i9.68519
E-ISSN: 2091-0576
P-ISSN: 2467-9100
Copyright (c) 2024 Asian Journal of
Medical Sciences
This work is licensed under a Creative
Commons Attribution-NonCommercial
4.0 International License.
Dhar, et al.: Role of Enhancers in cancer
2 Asian Journal of Medical Sciences | Sep 2024 | Vol 15 | Issue 9
https://doi.org/10.1016/j.molmed.2021.07.012
7. Wang X and Yue F. Hijacked enhancer-promoter and silencer-
promoter loops in cancer. Curr Opin Genet Dev. 2024;86:102199.
https://doi.org/10.1016/j.gde.2024.102199
8. Sun Z, Fan J, Dang Y and Zhao Y. Enhancer in cancer pathogenesis
and treatment. Genet Mol Biol. 2023;46(3):e20220313.
https://doi.org/10.1590/1678-4685-GMB-2022-0313
9. Belver L, Albero R and Ferrando AA. Deregulation of enhancer
structure, function, and dynamics in acute lymphoblastic
leukemia. Trends Immunol. 2021;42(5):418-431.
https://doi.org/10.1016/j.it.2021.03.005
10. Liau WS, Tan SH, Ngoc PC, Wang CQ, Tergaonkar V, Feng H,
et al. Aberrant activation of the GIMAP enhancer by oncogenic
transcription factors in T-cell acute lymphoblastic leukemia.
Leukemia. 2017;31(8):1798-1807.
https://doi.org/10.1038/leu.2016.392
11. Wang X, Xu J, Zhang B, Hou Y, Song F, Lyu H, et al. Genome-
wide detection of enhancer-hijacking events from chromatin
interaction data in rearranged genomes. Nat Methods.
2021;18(6):661-668.
https://doi.org/10.1038/s41592-021-01164-w
12. Yang M, Safavi S, Woodward EL, Duployez N, Olsson-Arvidsson L,
Ungerbäck J, et al. 13q12.2 deletions in acute lymphoblastic
leukemia lead to upregulation of FLT3 through enhancer
hijacking. Blood. 2020;136(8):946-956.
https://doi.org/10.1182/blood.2019004684
Authors’ Contributions:
RD, AK, and SK- Contributed equally toward the scripting of this editorial.
Work attributed to:
Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India, and Department of Biochemistry, Narayan Medical College, Gopal Narayan
Singh University, Sasaram, Bihar, India.
Orcid ID:
Dr. Ruby Dhar - https://orcid.org/0000-0003-3600-6554
Dr. Arun Kumar - https://orcid.org/0000-0002-8800-0296
Dr. Subhradip Karmakar - https://orcid.org/0000-0002-4757-8729
Source of Support: Nil, Conicts of Interest: None declared.
ResearchGate has not been able to resolve any citations for this publication.
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