The Role of Epigenetics in Cancer Biology

By Dr. Priyom Bose, Ph.D.Reviewed by Lily Ramsey, LLM

In mammals, epigenetics is important for the normal development and maintenance of tissue-specific gene expression.¹

A disruption in epigenetic processes could lead to malignant cellular transformation. Researchers use alterations in the epigenetic landscape as a hallmark of cancer. Epigenetic therapies are now regarded as a viable treatment strategy for multiple cancer types.

Image Credit: murat photographer/Shutterstock.com

Cancer and Epigenetics

Epigenetics involves a series of biological processes that regulate chromatin-mediated DNA templates.² Cancer is a multifactorial disease caused by epigenetic dysregulation, genetic variation, and environmental factors.

Abnormal post-translational modification processes and DNA or RNA methylation defects are two common epigenetic dysregulations associated with all cancer types.³

In eukaryotic cells, 146 bp of genomic DNA is wound around histone protein octamers (H3, H4, H2A, and H2B dimers) to form nucleosomes, which are basic structural units of chromatin.⁴

The nucleosome structure plays a crucial role in mRNA transcription. For example, a compact spatial structure of nucleosome promotes a universal inhibitory effect on mRNA transcription, while an accessible spatial structure allows RNA polymerases and transcriptional regulators to access the DNA.⁵

Epigenetics and cancer genetics are intricately associated with generating malignant phenotypes.⁶ For instance, epigenetic changes can trigger genetic mutations, and conversely, certain genetic mutations modify the epigenome. Protein complexes that regulate epigenetic modifications are classified as writers, readers, and erasers.

Epigenetic writers promote unique epigenetic chemical modifications to DNA or histones used as epigenetic markers. Methyl-CpG-binding domain proteins (MBPs) are epigenetic readers which can identify and interpret specialized domains of modified proteins. Chromatin-modifying enzymes are classified as erasers because they can remove epigenetic markers.³

What Role Does Epigenetics Play in Drug Discovery?

Mechanisms of Epigenetic Regulation in Cancer

Epigenetic processes, such as DNA methylation, RNA-mediated processes, and histone modification, trigger nucleosome remodeling through higher chromatin fibers (histone tails) folding.⁷

Chromatin stores and transmits epigenetic codes through post-translational histone modifications or DNA methylation. Regulatory factors and abnormal gene expression or irregular genome structure facilitate a transformation of normal cells or tissues into malignancies.⁸

Modern technologies, such as next-generation sequencing (NGS), bisulfite sequencing, chromatin immunoprecipitation (ChIP), and artificial intelligence (AI), have immensely improved the understanding of epigenetic regulation in cancer.⁹ Some important epigenetic modifications linked with cancer onset are discussed below:

DNA Methylation

DNA methylation is essential for precise gene expression regulation. Hyper- and hypo-methylation are independently associated with tumor progression. In contrast to hypo-methylated regions, hyper-methylated CpG islands in tumors are more frequently located in gene promoter regions.¹⁰

Researchers typically characterize cancer cells based on overall hypo-methylation and local hyper-methylation of promoters. Tumor suppressor gene CpG islands are associated with multiple carcinogeneses, including liver, prostate, breast, and small-cell bladder cancers.

DNA methyltransferase (DNMT) adds a methyl group to the C5 position cytosine residues during DNA methylation.¹¹ The epigenetic methylation groups differentiate normal cells from cancerous or other diseased cells.

DNMT is a conserved family of cytosine methylases that plays a crucial role in epigenetic regulation. The human genome encodes three DNMT subtypes, namely, DNMT1, DNMT3A, and DNMT3B, which have different functional roles.¹²

For example, DNMT1 maintains the pre-existing methylation pattern during DNA replication. It also maintains methylation patterns during normal and cancer cell replication.

DNMT3 involves de novo methylation and non-cytosine/guanine (CpG) methylation. DNMT3A and DNMT3B promote DNA methylation of previously unmethylated sites, which is associated with cancer cell survival, gene transcription, and regulation of biological functions of embryonic development.

The Future of Epigenetics

Histone Methylations

Histone methylation, an important determinant of complex chromatin state, is regulated by lysine demethylase (KDM) and lysine methyltransferase (KMT).³ In epigenetic regulation, KMT and KDM play the roles of writers and erasers, respectively.

The KMT uses S-adenosyl-L-methionine (methyl donor) to catalyze lysine methylation, which modifies core histones. However, the KDM family uses the Jumonji-C (JmjC) domain to catalyze demethylation via oxidation of the methyl group.

Histone Acetylation

Histone acetylation and deacetylation play important roles in the epigenetic regulation of gene transcription. Histone lysine acetyltransferases (HATs) and histone deacetylases (HDACs) are two enzyme families that regulate histone acetylation.¹³ HDAC is associated with various cancer types and different cancer stages.

RNA Epigenetics

Several studies have shown that protein-coding associated RNAs (e.g., tRNA mRNA, and rRNA), non-coding RNAs, such as microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) directly influence gene expression.

LncRNAs act as epigenetic drivers by recruiting chromatin regulators at specific chromatin loci.³ The specific regulatory pattern of functional lncRNAs could be exploited as cancer biomarkers and therapeutic targets.

Therapeutic Implications of Epigenetics in Cancer

Epigenetic modifications that are regulated by genomic organization are dynamic and reversible. Many small molecule inhibitors target chromatin- and histone-modifying enzymes to reverse tumour epigenetic alterations. This reversal could restore the normal epigenetic state and cure cancer.

The mRNA expression levels of DNMT are associated with sensitivity to inhibitors in different tumors. For example, DNMT3B inhibition elevates the sensitivity of the inhibitor in pancreatic cancer. However, in ovarian cancers, a higher DNMT expression enhances the efficacy of inhibitor treatment.³

Scientists used the potential reversibility of methyltransferase activity as a target for therapeutic interventions. Decitabine (DAC) and azacitidine (AZA) are the first clinically approved DNMT inhibitors (DNMTis) by the FDA to treat myelodysplastic syndromes (MDS).¹⁴

Multiple studies have shown that HDAC inhibition downregulates the expression of apoptosis-related proteins, and it can be used as a therapeutic target to control abnormal cell growth in cancer. HDAC inhibitors (HDACis) block HDAC deacetylase activity. Trichostatin A (TSA) is an inhibitor of class I and II HDACs, which has exhibited antitumor activity against breast cancer.¹⁵

Polycomb group protein (e.g., EZH2) is a type of KMT highly mutated in many tumor types. EZH2 has been identified as a potential therapeutic target because it involves a wide range of tumor processes, such as tumorigenesis, cancer immunity, cell cycle progression, metastasis, and apoptosis. GSK126 is an EZH2 inhibitor that restricts the growth of immune-deficient tumor cells.¹⁶

Several combined therapies targeting different epigenetic markers have been assessed. For example, a combinatorial treatment of vorinostat and AZA exhibited higher effectiveness in chronic myelomonocytic leukemia (CMML) than monotherapy.

Based on the promising preclinical and clinical trial results, scientists are currently focused on optimizing the combination administration regimen to reduce toxic side effects and increase efficacy.³

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