Epigenetic Therapy - An Overview

Introduction:

Genes are the major factors that play an important role in determining specialized traits in individuals. As humans, we inherit genes from our parents that determine our physical traits like eye color, height, and facial features. In addition, it also determines our psychological and behavioral characteristics like our personality and intellectual ability. Genes are a segment of DNA (deoxyribonucleic acid) that contains inherited genetic information. DNA or, more precisely, genes can become active and can be used to make RNA (ribonucleic acid), which is later converted into proteins. The process by which the information from a gene is used to make RNA or proteins is known as gene expression.

Gene expression is a regulated process that allows cells to respond to their changing environment. It controls when and how many proteins are to be made. Turning the genes on or off is achieved by gene regulation. Gene regulation is necessary for normal development and depends on epigenetic changes.

What Is Epigenetics?

Epigenetics studies inheritable changes in organisms caused by an alteration in gene expression. These epigenetic changes can cause cancer mainly due to genetic modifications that can influence gene expression. Unlike genetic changes, it is a reversible change that causes modifications to DNA without altering the sequence of DNA building blocks.

• DNA methylation.

• Histone modification.

• Non-coding RNAs.

Epigenetic changes are essential for normal development, but errors in the epigenetic mechanism can cause cancer or disease. Some common diseases caused by errors in epigenetic mechanisms include cancer, diabetes, leukemia (blood cancer), and other inherited diseases. Therefore, epigenetic therapy treats diseases associated with dysregulated epigenetic mechanisms.

What Is Epigenetic Therapy?

Epigenetic therapy uses drugs to reverse epigenetic changes or patterns associated with diseased cells. Unlike gene therapies, epigenetic therapies are reversible, as they are druggable for targeted therapies. Epigenetic therapy treats diseases by targeting and modulating epigenetic mechanisms. It treats several diseases, including cancer, heart disease, and diabetes (high blood sugar).

What Are the Targets for Epigenetic Therapies?

The main targets for epigenetic therapies are the epigenetic mechanisms that include:

• DNA methylation which is an epigenetic mechanism in which a methyl group is added to the cytosine base in DNA with the help of an enzyme called DNA methyltransferase. It is a heritable alteration that can lead to several diseases like cancer, cardiovascular disorders, atherosclerosis (plaque buildup in the artery walls), and neurovascular disorders.

• Histone modification which are proteins found in chromosomes. They bind to DNA and control gene expression. Histone modification is an epigenetic mechanism that impacts gene expression by adding histone modifiers or altering chromatin structure.

• Histone acetylation (addition of acetyl group to histone proteins).

• Histone methylation (adding or removing a methyl group to an amino acid in a histone tail).

• Histone phosphorylation (addition of phosphate group to histone proteins in the DNA).

• Histone ubiquitination (a process of transferring ubiquitin to histone core proteins).

• Histone citrullination (an epigenetic modification that converts histone arginine to citrulline).

• Aberrant profiles of histone modifications play an important role in the pathogenesis of many diseases.

What Are the Different Types of Epigenetic Drugs?

The different types of epigenetic drugs are:

• Methylation-Inhibiting Drugs: Methylation-inhibiting drugs like Azacitidine and Decitabine inhibit the enzyme DNA methyltransferase, which catalyzes the transfer of methyl group to DNA. They are used for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Although they are widely used epigenetic drugs, their application is restricted to cancer treatment due to their relative toxicity and poor chemical stability.

• HAT (Histone Acetyltransferase) Inhibitors: HAT inhibitors inhibit the catalytic activity of histone acetyltransferase in various diseases. Curcumin found in turmeric is one of the naturally occurring HAT inhibitors. Garcinol (a naturally occurring compound derived from the fruit garcinia India) and anacardic acid (a chemical compound found in the shell of cashew nut) are the other naturally occurring HAT inhibitors.

• Protein Methyltransferase Inhibitors: They inhibit the protein methyltransferase enzyme, which catalyzes the addition of a methyl group to the amino acids lysine or arginine. The enzymatic activity of protein methyltransferase is seen in inflammatory diseases, cancer, and neurodegenerative diseases.

• Histone Methylation Inhibitors: 3- Deazaneplanocin A is a histone methyltransferase EZH2 inhibitor that inhibits trimethylation on Histone H3. It is used in cancer treatment and is also effective in treating the Ebola virus.

• HDAC (Histone Deacetylase Inhibitors): HDAC inhibitors inhibit histone deacetylase enzymes. Vorinostat (suberoylanilide hydroxamic acid) is an FDA-approved HDAC inhibitor drug used to treat cutaneous T-cell lymphoma.

How Does Epigenetic Therapy Treat Cancer?

Aberrations in epigenetic mechanisms result in altered gene function and can lead to cancer development. Epigenetic mechanisms like DNA methylation and histone modification are essential in tumor formation. Cancers associated with aberrant epigenetic changes can be treated using epigenetic drugs. Cancer cells use epigenetic mechanisms like DNA methylation to inactivate tumor suppressor genes. Epigenetic drugs reactivate the tumor suppressor genes by inhibiting DNA methylation and killing cancer cells. Studies have reported that treatment with epigenetic drugs can help overcome chemotherapy resistance in certain cancers, including lung, breast, colorectal, and ovarian cancer.

What Are the Risks Associated With Epigenetic Therapy?

The common risks associated with epigenetic therapy include:

• Nausea.

• Vomiting.

• Fatigue.

• Constipation.

• Difficulty in breathing.

• Low levels of white blood cells.

What Are the Applications of Epigenetic Therapy?

Epigenetic therapy treats diseases like cancer, diabetes (high blood sugar), cardiovascular diseases, autism spectrum disorder, schizophrenia, anxiety, fear, and trauma. Epigenetic therapy also treats malignant mesothelioma and small-cell lung cancer. It is safer than other cancer treatments like chemotherapy since it has few side effects. Combining epigenetic therapy with other anticancer drugs increases the therapeutic effect of cancer treatments. Some risks are associated with epigenetic therapy, but they can be reduced by incorporating changes in lifestyle and diet.

Conclusion:

Epigenetic therapy can modify and treat aberrant epigenetic changes that cause various diseases. However, the efficacy of epigenetic therapy in improving overall survival may vary with each patient. Therefore, many clinical trials are still being conducted to determine its effect in various cases.