The activity of our genes is influenced not only by the DNA sequence itself but also by mechanisms that control how genes are expressed. This field of study is called epigenetics, and it explores changes in gene activity that do not involve alterations to the underlying DNA code. These modifications can determine which genes are turned on or off, or how much protein they produce. Epigenetics has a significant connection to human health and disease, particularly in cancer development.
Understanding Epigenetics
Epigenetics focuses on modifications to DNA and associated proteins that regulate gene activity without changing the actual DNA sequence. The term “epi-” means “on” or “above” in Greek, indicating that these factors exist beyond the genetic code. These epigenetic changes create an additional layer of information that influences how genes are used in different cells. This regulation ensures each cell type produces only the proteins necessary for its specific function, such as bone-building proteins in bone cells.
One primary epigenetic mechanism is DNA methylation, where small chemical tags called methyl groups are added to DNA building blocks. When these methyl groups are present on a gene’s promoter region, that gene is turned off or silenced, preventing protein production. This acts like a “switch” that can stably turn off genes.
Another significant mechanism involves histone modifications. DNA is tightly wrapped around proteins called histones, forming structures called nucleosomes. Histones can be modified by the addition or removal of chemical groups, such as acetyl or methyl groups, which influences how tightly the DNA is wound. If the DNA is tightly packed, genes in that region are less accessible and are turned off; if it’s loosely packed, genes are more accessible and can be turned on. This process works like a “dimmer switch,” adjusting gene activity by controlling DNA accessibility.
Non-coding RNAs (ncRNAs) represent a third epigenetic mechanism. These RNA molecules do not carry instructions for making proteins but instead play a regulatory role in gene expression. Examples include microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which can influence gene activity by regulating messenger RNA or interacting with other gene-controlling complexes. These ncRNAs contribute to the complex network that controls gene expression.
Epigenetic Changes in Cancer Development
Normal epigenetic patterns are precisely regulated, but in cancer cells, these patterns become disrupted, contributing to uncontrolled cell growth and proliferation. These disruptions, often called epimutations, can occur early in cancer development and play a role in its progression. Unlike genetic mutations that alter the DNA sequence itself, epigenetic changes modify how the DNA is read and expressed.
One common epigenetic alteration in cancer is hypermethylation, where an excessive number of methyl groups are added to the promoter regions of tumor suppressor genes. Tumor suppressor genes, such as p53 and BRCA1, normally act to prevent cancer by regulating cell division, repairing DNA damage, or initiating programmed cell death. When these genes become hypermethylated, they are silenced, losing their protective function and allowing abnormal cells to grow unchecked. For instance, BRCA1 promoter hypermethylation can lead to reduced gene expression, promoting cancer development.
Conversely, hypomethylation, which is a decrease in DNA methylation, can also contribute to cancer. This occurs in oncogenes, which are genes that promote cell growth. When oncogenes are hypomethylated, they become overly active, leading to increased cell proliferation and tumor development. Hypomethylation can also affect regions involved in tumor invasion and metastasis.
Histone modifications are altered in cancer cells, affecting how DNA is packaged and accessed. For example, changes in histone acetylation can lead to cancer development; overexpression of histone deacetylases (HDACs) can drive tumor growth by altering gene expression. Histone methylation patterns are also disrupted, with disruptions in enzymes that add or remove methyl groups leading to abnormal gene expression and genome instability. These modifications can influence the expression of both oncogenes and tumor suppressor genes.
Non-coding RNAs also play a role in cancer when their expression is altered. MicroRNAs (miRNAs) can act as either oncogenes or tumor suppressors, depending on which genes they target. Similarly, long non-coding RNAs (lncRNAs) can promote cancer progression by affecting gene activity. These dysregulations in ncRNA expression contribute to the uncontrolled cellular processes seen in cancer.
Environmental factors can influence these epigenetic changes. Diet, lifestyle choices like smoking, exposure to pollutants, and even stress can impact the epigenome. For example, environmental carcinogens can induce epigenetic changes that contribute to disease development. These external influences can either promote or inhibit cancer development by altering DNA methylation, histone modifications, and non-coding RNA regulation.
Epigenetic Therapies for Cancer
Understanding the role of epigenetic changes in cancer has opened new avenues for treatment, leading to the development of “epigenetic drugs.” These therapies aim to reverse or correct the abnormal epigenetic marks found in cancer cells, often by adjusting how cells work rather than directly killing them like traditional chemotherapy. This approach can sensitize cancer cells to existing treatments or offer new therapeutic options.
One class of epigenetic drugs is DNA methyltransferase inhibitors (DNMT inhibitors), such as azacitidine and decitabine. These drugs work by reducing DNA methylation, particularly the hypermethylation that silences tumor suppressor genes. When incorporated into DNA, they inhibit DNMT enzymes, leading to a decrease in overall DNA methylation. This allows previously silenced tumor suppressor genes to become active again, restoring their normal function and inhibiting cancer cell growth. These drugs are approved for treating myelodysplastic syndromes, a type of leukemia.
Another category of epigenetic drugs includes histone deacetylase (HDAC) inhibitors, such as vorinostat. HDACs are enzymes that remove acetyl groups from histones, leading to a more compact DNA structure and gene silencing. By inhibiting HDAC activity, vorinostat increases histone acetylation, which relaxes the chromatin structure. This allows for the re-expression of tumor suppressor genes and other genes that can inhibit cancer cell growth. Vorinostat is approved for treating cutaneous T-cell lymphoma.
Epigenetic therapies can be used alone or in combination with traditional cancer treatments like chemotherapy and immunotherapy. Combining epigenetic drugs with other therapies can enhance anti-tumor effects, reduce treatment resistance, and improve patient outcomes. For instance, epigenetic modifiers can make cancer cells more susceptible to chemotherapy by reactivating silenced genes or by making them more visible to the immune system. Ongoing research is focused on developing more targeted and effective epigenetic drugs, as well as optimizing combination strategies to address the complexities of cancer.