Epigenetics in Cancer: Mechanisms, Oncogenesis, and Therapeutic

Potential

Shiyuan Huang

Merchiston International School, Shenzhen, China

Keywords: Epigenetics, DNA Methylation, Cancer Therapy.

Abstract: Epigenetics are able to influence gene expression without changing the nitrogenous base sequence of DNA.

These modifications include DNA methylation, histone modifications, chromatin remodeling, and non-coding

RNA regulation, which all contributes to cancer development. Abnormal epigenetic changes can lead to

oncogene activation and tumor suppressor genes (TSGs) silencing, making epigenetics promising therapeutic

targets. This review explores the mechanisms of these four epigenetic processes, their roles in carcinogenesis,

and current strategies for epigenetic therapy. It highlights the importance of understanding these mechanisms

to address challenges such as high toxicity and low specificity, and to advance precision medicine in cancer

treatment.

1 INTRODUCTION

Cancer is a type of disease described as uncontrolled

cell division which result in spread of abnormal cells

and formation of tumor. Although genetic mutations

are the primary and most well-known cause of cancer,

epigenetics has emerged as a new focus in

oncogenesis over the past decade. Epigenetic

modifications alter the gene expression by

influencing the ability of DNA to access to

transcription and translation machinery. Because

epigenetic changes are reversible, they can cause

abnormal gene expression, leading to the oncogenes

being over-expressed or the tumor suppressor genes

(TSGs) being under-expressed, which is key of

causing cancer. Given the role of epigenetics in

actively causing cancer, the mechanisms underlying

these changes and the potential for epigenetic

treatments have become hot topics.

This review explores four key epigenetic

mechanisms: DNA methylation, histone

modifications, chromatin remodeling, and non-

coding RNA regulation. It then examines the effects

of these epigenetic alterations in causing cancer,

including the oncogene activation and TSGs

silencing. The therapeutic potential of epigenetic

interventions is discussed, with a focus on targeting

epigenetic "writers," "readers," and "erasers."

While most of these interventions have

demonstrated potential in preclinical studies, they

require further optimization to address toxicity and

specificity concerns. This review provides

theoretical insights and practical recommendations

for the study of epigenetics in the context of cancer

development and treatment.

2 EPIGENETIC MECHANISM

2.1 DNA Methylation

DNA methylation involves the adding a methyl group

(CH3) to the 5th carbon of the base, cytosine, and

turning it to 5-methylcytosine. Depending on the

location of methylation, it can either inhibit or

enhance gene expression (Tibben & Rothbart 2024).

The proteins methyltransferases (DNMTs) conduct

the addition of methyl groups, whereas the removal

of methyl groups is facilitated by TET proteins and

the base excision repair (BER) pathway (Wyatt &

Pittman 2006). Methylation significantly impacts the

genome. Under random conditions, the probability of

a particular dinucleotide occurring in a DNA

sequence is 1/16, or 6.25%. However, CpG

dinucleotides, composed of cytosine and guanine

linked by a phosphodiester bond, occur at a frequency

of only 1% in the genome. This underrepresentation

is primarily due to the accidental deamination. When

Huang, S.

Epigenetics in Cancer: Mechanisms, Oncogenesis, and Therapeutic Potential.

DOI: 10.5220/0014400300004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 69-74

ISBN: 978-989-758-789-4

a normal cytosine undergoes deamination, it becomes

an uracil, and uracil DNA glycosylase (UDG) can

rapidly repair uracil back to cytosine. However, when

a 5-methylcytosine deaminate, it turns to a thymine,

but thymine DNA glycosylase (TDG) repairs thymine

at a slower rate, which is insufficient to counteract the

high rate of transcription. Consequently, CpG

dinucleotides are underrepresented in the genome

(Maiti & Drohat 2011, Silveira et al. 2024). DNA

methylation at gene promoters generally inhibits

transcription. When cytosine residues within

promoters are methylated, the 5-methylcytosine

makes the nucleosomes to be more stable and

prevents transcription machinery such as

transcriptional factors and polymerase from binding

to the DNA. In contrast, gene body methylation

(GbM) prevents the binding of repressive chromatin-

modifying complexes thereby promotes transcription

(Williams et al. 2023).

2.2 Histone Modification

The three types of histone modifications are

acetylation, methylation, and phosphorylation. They

influence expression of proteins through altering

structure of chromatin and impacts the DNA’s

potential to bind to proteins that assist transcription to

happen.

Histone acetylation is adding of acetyl groups on

histone, it is done by the protein histone

acetyltransferases (HATs). Additionally, acetyl

groups can be removed by histone deacetylases

(HDACs). Acetylation occurs on the lysine residues

of histone. Histone is positively charged, and DNA is

negatively charge, meaning they are connected by

electrostatic attraction. Acetyl groups can mask the

positive charge of histone and weakening the

electrostatic interactions between histones DNA. This

modification loosens the chromatin structure,

allowing transcription factors and other regulatory

proteins to access the DNA more easily, thereby

promoting gene expression (Liebner et al. 2024).

Histone methylation involves the incorporation of

methyl groups to lysine or arginine residues,

catalyzed by histone methyltransferases (HMTs) and

removed by histone demethylases. On lysine residue,

maximum of three methyl groups can be added,

resulting in four states: unmethylated, mono-

methylated, di-methylated, and tri-methylated.

Whereas only two states of mono-methylated or di-

methylated exist on arginine residue (Tollefsbol,

2023). Histone methylation can influence the basicity

and hydrophobicity of histones, thereby affecting the

affinity of certain effector proteins that either activate

or repress gene expression, such as transcription

factors (Tollefsbol 2023). The specific impact

depends on how many methyl groups is added and on

which residue it is added. For instance, trimethylation

of histone H3 at lysine 4 promotes transcription to

happen. On the other hand, trimethylation of histone

H3 at lysine 27 can prevent expression and is often

found in regions of condensed chromatin (Cavalheiro

et al. 2021).

Histone phosphorylation, typically occurring on

serine or threonine residues, can directly alter

histone-DNA interactions, recruit other proteins that

modify chromatin shape, and impact the addition of

other epigenetic markers. For example,

phosphorylation of histone H2AX at serine 139 is a

key marker of DNA double-strand breaks and is

involved in the DNA damage response. This

modification helps recruit repair proteins to where

damages occur, ensuring genomic stability (López-

Hernández et al. 2025).

2.3 Chromatin Remodeling

Chromatin-remodeling complexes, which use the

energy from ATP to change the shape, composition,

or location of nucleosomes, are responsible for

chromatin remodeling (Hota & Bruneau 2016). These

complexes can slide nucleosomes along the DNA,

eject them from specific sites, or incorporate histone

variants, thereby modulating DNA accessibility.

When chromatin is remodeled into a more open state,

transcription factors and RNA polymerase can access

the DNA more easily, leading to gene activation.

Conversely, a more compact chromatin structure

restricts access, resulting in gene repression (Alendar

& Berns 2021).

2.4 Non-Coding RNA

There are two categories of non-coding RNAs: short

ncRNAs, which include microRNAs (miRNAs) and

small interfering RNAs (siRNAs), and long non-

coding RNAs (lncRNAs). These ncRNAs can

modulate gene expression through diverse

mechanisms. Short non-coding RNAs function at the

post-transcriptional stage by attaching to the 3-prime

untranslated regions (3' UTRs) of specific mRNAs.

which can lead to mRNA degradation or inhibit

translation (Zhang et al. 2024). Long ncRNAs

(lncRNAs) can recruit chromatin-modifying

complexes, resulting in histone modifications.

Additionally, lncRNAs can interact with proteins

BEFS 2025 - International Conference on Biomedical Engineering and Food Science

such as methyltransferases and acetyltransferases to

add or remove methyl or acetyl groups (Li J et al.

2024).

3 ROLE OF EPIGENETICS IN

CANCER DEVELOPMENT

3.1 DNA Methylation

DNA methylation primarily acts through two key

mechanisms to cause cancer: regional

hypermethylation and global hypomethylation.

Regional hypermethylation frequently occurs in the

promoter regions of TSGs, resulting in the

inactivation of these genes. This silencing disrupts the

normal regulatory functions that would otherwise

inhibit cell proliferation and promote apoptosis,

thereby contributing to uncontrolled cell division (Su

et al. 2018). On the other hand, global

hypomethylation affects repetitive elements in the

genome, such as retrotransposons. This widespread

hypomethylation can lead to chromosomal

rearrangements and genome instability. The absence

of methyl group in these regions may activate

transposable elements, causing insertional

mutagenesis and further disrupting the normal

functioning of genes (Jordà et al. 2017). Additionally,

altered DNA methylation patterns can also affect the

tumor microenvironment, influencing the behavior of

immune cells and contributing to immune evasion by

cancer cells (Zhong et al. 2023).

3.2 Histone Modification

Abnormal acetylation patterns can disrupt the normal

level of oncogenes and TSGs. High level of histone

deacetylases (HDACs) can cause hypoacetylation of

histones, as a result TSGs inactivated, such as p53. In

contrast, hyperacetylation of oncogenes can boost

their expression and accelerate cancer progression

(Bu et al. 2024). Histone methylation plays a more

intricate role in cancer, with different methylation

sites exerting distinct effects. For instance, mutations

in H3K27 methyltransferases, such as EZH2, have

been implicated in many cancers, including breast

cancer and hepatocellular carcinoma (Gu et al.2022,

Ning et al.2016).

3.3 Chromatin Remodeling

Aberrant chromatin remodeling can result in the

activation of oncogenes and the silencing of TSGs.

For example, a number of cancers, including

leukemia, prostate cancer, and neurodevelopmental

disorders, are known to have mutations in parts of the

SWI/SNF chromatin remodeling complex. These

alterations have the potential to impair the complex's

regular operation and alter gene expression, which

encourages carcinogenesis. (Kadoch et al. 2013).

Moreover, SWI/SNF participates in the regulation

promoters, which are critical for maintaining the

expression of oncogenic transcription factors.

Dysregulation of these complexes can result in the

aberrant activation of oncogenic pathways.

Additionally, chromatin remodeling can influence the

microenvironment of tumors by affecting the immune

systen and the response to DNA damage. This can

lead to immune evasion and increased genomic

instability, further contributing to cancer progression

(Kadoch et al. 2013).

3.4 Non-Coding RNA

Non-coding RNAsnc (RNAs) can act as both tumor

suppressors and oncogenes depending on their targets

and cellular context. For example, the abnormal level

of expression of microRNAs is frequently observed

in patients with cancer. These miRNAs can either

promote tumor growth by silencing TSGs or inhibit

oncogenic pathways by targeting oncogenes. Long

non-coding RNAs (lncRNAs) can sequester

miRNAs, thereby diminishing the regulatory impact

of miRNAs on their target mRNAs (John et al. 2025,

Kim et al. 2024).

4 EPIGENETIC THERAPIES FOR

CANCER TREATMENT

4.1 Targeting Epigenetic Writers

Epigenetic writers are proteins that add epigenetic

markers to target sites, thereby influencing gene

expression.

4.1.1 DNA Methyltransferase Inhibition

DNA methyltransferases (DNMTs) are important

proteins that can bring of methyl groups to DNA.

Methylation of the promoters of TSGs often leads to

inactivation. This mechanism is frequently

Epigenetics in Cancer: Mechanisms, Oncogenesis, and Therapeutic Potential

dysregulated in cancer, making DNMTs attractive

therapeutic targets. DNMT inhibitors, such as

azacitidine and decitabine, have been extensively

studied and are now approved for the treatment of

hematologic malignancies. These nucleoside analogs

are incorporated into DNA, inhibiting DNMTs and

leading to DNA demethylation, which in turn

reactivates silenced TSGs. However, their efficacy in

solid tumors has been limited due to toxicity and

pharmacokinetic challenges (Ren et al. 2023).

4.1.2 Histone Methyltransferase Inhibition

Histone methyltransferases (HMTs) are proteins that

bring methyl groups to histone, thereby influencing

gene expression. Among these, HMTs such as EZH2

and DOT1L have been identified as critical targets in

cancer therapy. EZH2 inhibitors, like tazemetostat,

have demonstrated significant efficacy in cancers

with EZH2 mutations or loss of SMARCB1. They

achieve this by reducing H3K27me3 levels and

reactivating target genes. Similarly, DOT1L

inhibitors, such as pinometostat, have shown

antitumor activity in MLL-rearranged leukemia by

targeting H3K79 methylation.These inhibitors have

shown promise in clinical trials. However, challenges

remain in optimizing their use, particularly in solid

tumors (Li D et al. 2024).

4.2 Targeting Epigenetic Readers for

Cancer Therapy

Epigenetic readers are proteins that identify and

attach to particular epigenetic modifications on DNA

and histones, subsequently affecting gene expression

and cellular outcomes. The bromodomain and extra-

terminal domain (BET) family consists of BRD2,

BRD3, BRD4, and BRDt, is a key group of epigenetic

readers. These proteins specifically recognize

acetylated lysine residues, making them attractive

targets for cancer therapy. BET inhibitors, such as

JQ1, have been developed to selectively target these

proteins, resulting in the downregulation of

oncogenic targets like MYC. However, concerns over

toxicity and the development of resistance have

prompted the search for second-generation inhibitors.

Natural compounds, particularly those derived from

plants and marine sources, have emerged as potential

alternatives. For example, naringenin triacetate from

bitter orange, resveratrol from grapes, and magnolol

from the magnolia tree have shown promise in

targeting BET proteins. These natural compounds

offer the advantages of lower toxicity and potential

synergistic effects when combined with other

therapies (Damiani et al. 2020).

4.3 Targeting Epigenetic Erasers for

Cancer Therapy

Epigenetic erasers eliminate modifications on DNA

or histones, thus influencing gene expression.

Notable epigenetic erasers consist of TET enzymes,

histone lysine demethylases (HDMs), and histone

deacetylases (HDACs). The TET enzymes are

essential for DNA demethylation as they restrict

DNMT1's ability to recognize 5-

hydroxymethylcytosine (5-hmC). As a result,

dividing cells gradually lose their methylation.

Lysine-specific demethylase (LSD) and JmjC

domain-containing lysine demethylases are the two

groups of histone lysine demethylases (HDMs).

LSD1 (KDM1A) and LSD2 (KDM1B) remove

methyl groups from histone lysines through their

oxidase-like domains. These enzymes are often

overexpressed in cancers such as prostate, breast, and

colorectal cancer (Yang et al. 2016).

5 COMBINED TREATMENT OF

EPIGENETIC THERAPY WITH

OTHER CANCER THERAPIES

5.1 Epigenetic Therapy and

Chemotherapy

Epigenetic therapies have demonstrated the potential

to enhance the effects of chemotherapy. For example,

histone deacetylase inhibitors (HDACi) have

demonstrated ability to amplify the effects of

chemotherapeutic agents, for example, topotecan, in

small cell lung cancer. Similarly, combining DNA

methyltransferase inhibitors like decitabine with

cytarabine has exhibited synergistic effects in

leukemia cell lines. These combinations can

overcome chemotherapy resistance by reactivating

silenced TSGs and enhancing drug-induced apoptosis

(Li et al. 2017).

5.2 Epigenetic Therapy and

Radiotherapy

Epigenetic modifications can sensitize cancer cells to

radiotherapy. For instance, HDAC inhibitors seemed

to enhance response to DNA damage induced by

radiation, which causes increased cells to die. This

BEFS 2025 - International Conference on Biomedical Engineering and Food Science

combination takes advantage of the ability of

epigenetic drugs to modulate the tumor

microenvironment and thereby improve the efficacy

of radiation therapy (Camphausen & Tofilon 2007).

5.3 Epigenetic Therapy and

Immunotherapy

Combining epigenetic therapies with immunotherapy

has emerged as a positive treatment to enhance

antitumor immunity. Epigenetic drugs can upregulate

tumor antigens and major histocompatibility complex

(MHC) molecules, thereby improving the ability to

identify and killing of cancer cells by immune cells.

For instance, dual targeting of EZH2 and HDAC with

tazemetostat and belinostat has been shown to

promote immunogenicity in certain cancers (Marx et

al. 2005).

5.4 Epigenetic Therapy and Hormone

Therapy

In the context of hormone therapy, HDAC inhibitors

have shown potential to enhance therapeutic effects

and overcome drug resistance. For instance, in breast

cancer, HDAC inhibitors have consistently

demonstrated their ability to disrupt estrogen-

receptor signaling pathways in estrogen-receptor-

positive (ER+) breast cancer (Margueron et al. 2004).

6 CONCLUSION

To conclude, the four types of epigenetic mechanisms

including DNA methylation, histone modifications,

chromatin remodeling, and non-coding RNAs

actively cause cancer. These epigenetic alterations

can trigger oncogenes being overexpressed or TSGs

being under-expressed. Moreover, environmental

factors like smoking, diet, and pollution can induce

such epigenetic changes, thereby further contributing

to cancer risk. Despite the immense potential of

epigenetics as a target for cancer treatment, current

epigenetic therapies face challenges of high toxicity

and low specificity. This is partly due to the broad-

spectrum nature of drugs such as DNMT inhibitors

and HDAC inhibitors. Future research should focus

on optimizing drug doses and developing targeted

delivery methods—such as nanoparticles—to

improve efficacy while minimizing effects on non-

cancerous cells. Overall, addressing these limitations

and exploring new strategies will be essential for

advancing epigenetic cancer therapies.

REFERENCES

Alendar, A. & Berns, A. 2021. Sentinels of chromatin:

chromodomain helicase DNA-binding proteins in

development and disease. Genes & Development

35(21-22):1403-1430.

Bu, S., Ye, T., & Gao, H.,et al. 2024. Histone methylation

and acetylation in cancer: mechanism, progression, and

targets. ONCOLOGIE.

Camphausen, K. & Tofilon, P. J. 2007. Inhibition of

Histone Deacetylation: A Strategy for Tumor

Radiosensitization. Journal of Clinical Oncology

25(26): 4051-4056.

Cavalheiro, G. R., Pollex, T., & Furlong, E. E. 2021. To

loop or not to loop: what is the role of TADs in enhancer

function and gene regulation? Current Opinion in

Genetics & Development 67:119-129.

Damiani, E., Duran, M. N., & Mohan, N., et al. 2020.

Targeting Epigenetic ‘Readers’ with Natural

Compounds for Cancer Interception. Journal of Cancer

Prevention 25(4): 189-203.

Gu, Y., Zhang, X., & Yu, W., et al. 2022. Oncogene or

Tumor Suppressor: The Coordinative Role of Lysine

Methyltransferase SET7/9 in Cancer Development and

the Related Mechanisms. Journal of Cancer 13(2):623-

640.

Hota, S. K. & Bruneau, B. G. 2016. ATP-dependent

chromatin remodeling during mammalian

development. Development 143(16):2882-2897.

John, A., Almulla, N., & Elboughdiri, N., et al. 2025. Non-

coding RNAs in Cancer: Mechanistic insights and

therapeutic implications. Pathology - Research and

Practice 266:155745.

Jordà, M., Díez-Villanueva, A., & Mallona, I., et al. 2017.

The epigenetic landscape of Alu repeats delineates the

structural and functional genomic architecture of colon

cancer cells. Genome Research 27(1): 118-132.

Kadoch, C., Hargreaves, D. C., & Hodges, C., et al. 2013.

Proteomic and bioinformatic analysis of mammalian

SWI/SNF complexes identifies extensive roles in

human malignancy. Nature Genetics 45(6): 592-601.

Kim, S. Y., Na, M. J., & Yoon, S., et al. 2024. The roles and

mechanisms of coding and noncoding RNA variations

in cancer. Experimental & Molecular Medicine 56(9):

1909-1920.

Li, D., Peng, X., & Hu, Z., et al. 2024. Small molecules

targeting selected histone methyltransferases HMTs for

cancer treatment: Current progress and novel strategies.

European Journal of Medicinal Chemistry 264:115982.

Li, J., Hao, D., & Wang, L., et al. 2017. Epigenetic targeting

drugs potentiate chemotherapeutic effects in solid

tumor therapy. Scientific Reports 7(1):4035.

Li, J., Wang, X., & Wang, H. 2024. RNA modifications in

long non-coding RNAs and their implications in cancer

Epigenetics in Cancer: Mechanisms, Oncogenesis, and Therapeutic Potential

biology. Bioorganic & Medicinal Chemistry

113:117922.

Liebner, T., Kilic, S., & Walter, J., et al. 2024. Acetylation

of histones and non-histone proteins is not a mere

consequence of ongoing transcription. Nature

Communications 15(1):4962.

López-Hernández, L., Toolan-Kerr, P., & Bannister, A. J.,

et al. 2025. Dynamic histone modification patterns

coordinating DNA processes. Molecular Cell 85(2):

225-237.

Maiti, A. & Drohat, A. C. 2011. Thymine DNA

Glycosylase Can Rapidly Excise 5-Formylcytosine and

5-Carboxylcytosine. Journal of Biological Chemistry

286(41): 35334-35338.

Margueron, R., Duong, V., & Bonnet, S., et al. 2004.

Histone deacetylase inhibition and estrogen receptor

alpha levels modulate the transcriptional activity of

partial antiestrogens. Journal of Molecular

Endocrinology 32(2):583-594.

Marx, G. M., Steer, C. B., & Harper, P. G. 2005. Reply to

the letter “Limitations of bedside estimates of renal

function”, by M. J. Dooley and S. G. Poole

doi:10.1093/annonc/mdi173. Annals of Oncology

166:990.

Ning, B., Li, W., & Zhao, W., et al. 2016. Targeting

epigenetic regulations in cancer. Acta Biochimica et

Biophysica Sinica 48(1):97-109.

Ren, L., Yang, Y., & Li, W., et al. 2023. Recent advances

in epigenetic anticancer therapeutics and future

perspectives. Frontiers in Genetics 13:1085391.

Silveira, A. B., Houy, A., & Ganier, O., et al. 2024. Base-

excision repair pathway shapes 5-methylcytosine

deamination signatures in pan-cancer genomes. Nature

Communications 15(1):9864.

Su, J., Huang, Y.H., & Cui, X., et al. 2018. Homeobox

oncogene activation by pan-cancer DNA

hypermethylation. Genome Biology 19(1):108.

Tibben, B. M. & Rothbart, S. B. 2024. Mechanisms of DNA

Methylation Regulatory Function and Crosstalk with

Histone Lysine Methylation. Journal of Molecular

Biology 436(7): 168394.

Williams, C. J., Dai, D., & Tran, K. A., et al. 2023. Dynamic

DNA methylation turnover in gene bodies is associated

with enhanced gene expression plasticity in plants.

Genome Biology 24(1): 227.

Wyatt, M. D. & Pittman, D. L. 2006. Methylating agents

and DNA repair responses: Methylated bases and

sources of strand breaks. Chemical Research in

Toxicology 19(12): 1580-1594.

Yang, A.Y., Kim, H., & Li, W., et al. 2016. Natural

compound-derived epigenetic regulators targeting

epigenetic readers, writers and erasers. Current Topics

in Medicinal Chemistry 16(7): 697-713.

Zhang, Y., Zhan, L., & Jiang, X., et al. 2024.

Comprehensive review for non-coding RNAs: From

mechanisms to therapeutic applications. Biochemical

Pharmacology 224: 116218.

Zhong, F., Lin, Y., & Zhao, L., et al. 2023. Reshaping the

tumour immune microenvironment in solid tumours via

tumour cell and immune cell DNA methylation: from

mechanisms to therapeutics. British Journal of Cancer

129(1): 24-37.

BEFS 2025 - International Conference on Biomedical Engineering and Food Science