Epigenetic Processes in Carcinogenesis

By: Annie Hu


The concept of nature vs. nurture is a common yet age-old debate. “Nature” refers to the genetic traits a child is born with, while “nurture” reflects their life experiences. For centuries, we have debated which plays a bigger role in shaping human personality and health. But at this time, the general consensus is that they both play an important role in human development. What if we applied this same concept, that both nature and nurture affect development, not only to psychology, but also to genetics? This is where epigenetics, defined as the study of changes in addition to those in genetic sequence (both influence gene expression), comes into the picture. The genetic code is the basis of the “nature” portion of the main idea, and epigenetics suggests that experiences and “nurture” affect the expression of these genes. This revolutionary paradigm, that genes are not set in stone and can be altered through experiences, is the central idea of epigenetics. These experiences could be lifestyle changes, biological events, or chemical exposures that cause changes within the body.


Epigenetic changes are defined as anything that changes gene activity without actually changing the DNA sequence. Certain experiences, habits, and lifestyle choices have been found to help prevent diseases, like cancer. They do this by causing a multitude of favorable physical and chemical changes that alter gene expression by promoting helpful genes. Epigenetic changes affect the makeup of the epigenome, as they are unique to each individual and their experiences. The uniqueness of each person’s epigenome is called their “epigenetic signature”.


Image Credit: Flickr @ Ultrabem

The most extensive research conducted on epigenetic changes and disease has been in cancer development. Carcinogenesis, the onset of cancer, was previously thought to be the sole product of genes. This idea is being replaced, as it becomes clearer and clearer that changes in the epigenome are a hallmark of cancer development, alongside previously identified genetic risk factors. The interesting part about these cancer preventing or promoting epigenetic changes, is that they are heritable and can be passed from cell to cell during cell division. As heritable epigenetic changes in gene expression occur, they continue to be passed on. This heritability is important to note, as it means negative changes that occur can become out of control and may result in elevated cancer risk.


But what epigenetic changes have been identified in cancer cells? In normal somatic (body) cells, there is a complex maintenance of balance in the epigenetic landscape. Genetic markers help us determine if this balance is ever thrown off. You may have heard of homeostasis, which is the body’s ability to maintain its regular functions through a delicate balance. Chemical and physical interactions in the epigenome must regulate one another to keep cells functioning and avoid disease-causing disruptions. If this balance is disrupted, and genes are changed out of balance, there can be disastrous consequences.


The best known epigenetic marker in the epigenetic landscape is DNA methylation. DNA methylation is the addition or removal of CH3, occurring in sequences where the base Cytosine comes before a Guanine base (these sites are called dinucleotide CpG’s). CpG’s sometimes are grouped together in the genome and are called CpG islands. DNA methylation plays a role in controlling gene activities and the structure of the nucleus (which houses DNA). Methylation is crucial to silencing genes that are only expressed in malignant cancer tumors, thus preventing tumor growth. Methylation regulation of repetitive DNA sequences can help stabilize the chromosome and genetic code by preventing mutations, as repetitive sequences are hotspots for DNA evolution. Abnormal DNA methylation can be upregulated in some areas and downregulated in others. This methylation imbalance has been known to occur in cancer cells and can affect healthy gene activities.


Overall, we see a downregulation of methylation in the epigenome in cancer cells. Without global (overall) epigenetic DNA methylation, nuclear deformations may occur as the DNA becomes unstable. This global hypomethylation (lower-than-normal levels of methylation) is one of the most studied epigenetic changes in tumor cells. A decrease in overall DNA methylation content has been linked to the progression of benign (less risky) to malignant (dangerous) cancers. But even though the overall genome has lower levels of methylation, some regions show a trend of becoming hypermethylated (or having increased methylation). So as the whole genome decreases methylation, these specific regions increase. This hypermethylation in certain regions (especially CpG’s) helps tumor progression by inactivating tumor-suppressor genes.


Another epigenetic change that has been intensively studied is chromatin modification. Chromatin is condensed DNA. The DNA gets condensed by wrapping it around histones which are ball shaped proteins. This protein complex of histones and DNA is bundled to form chromosomes in the nucleus. Perhaps the most detectable changes in chromatin are histone modifications, which are identified using mass spectrometry. Mass spectrometry is an analytical technique that measures the amount of different masses present within a sample. Constituents of a substance can be broken down into separate masses, and frequency of their occurrence can be measured. For example, the number of amino acids in a protein can be measured by accounting for the prevalence of each mass (which is specific to one particular amino acid). Histone modifications occur within the histone constituents of proteins, the variants of those proteins, and residues. Methylation of histones is one of the few ways that nuclear processes may be affected to promote cancer. The effect of histone methylation differs by the amino acid types making up the histone proteins. Amino acid frequency is measurable by mass spectrometry. Correct gene transcription, DNA repair after mutation, and replication of cells are all possibly affected by modifications to histones given how closely they are related to DNA. For example, histones H3 and H4 may be hypermethylated in cancer cells and result in silencing important tumor-suppressor genes.


Unlike genetic changes, epigenetic changes are potentially reversible, leading to promising developments in epigenetic therapeutics. For example, epigenetically silenced tumor suppressor genes can be roused with the help of drugs and therapy. The tumor suppressor genes (as earlier mentioned) that were silenced as a result of hypermethylation in CpG islands can be treated. Demethylating drugs can counter the tumor-promoting activity in these CpG’s. These agents have already been approved for use in some cancers, like leukemia. There are other epigenetic drugs that have been identified, like Histone Deacetylase (HDAC) inhibitors for inducing normal cell cycle processes in counter to the nuclear changes accompanying histone modifications. However, both demethylating drugs and HDAC inhibitors produce results that are not yet studied in depth, and some cases show that they could even promote tumor growth, having a somewhat paradoxical effect.


Image Credit: Elias Sch. From Pixabay

Besides the genetic factors that people are born with, chemical and physical changes within cells can also affect gene expression. Thus, cancer, one of the most commonly studied diseases when it comes to epigenetics, is the result of acquired changes as well as genetic code. DNA methylation and histone modifications are two epigenetic processes which directly influence gene expression, nuclear processes, and cellular behavior. But because these acquired epigenetic changes are not permanent, therapies like demethylating agents and HDAC inhibitors hold promise for the future of treating cancer. Though these treatments are still being developed, the evolving concept of being able to change genetic fate remains an intriguing one.


Citations:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1392256/


https://developingchild.harvard.edu/resources/what-is-epigenetics-and-how-does-it-relate-to-child-development/#:~:text=%E2%80%9CEpigenetics%E2%80%9D%20is%20an%20emerging%20area,It's%20nearly%20always%20both!


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802667/


https://www.roswellpark.org/sites/default/files/tomasi_paper_2_5-1-14_esteller_nejm_2008_epigenetics_in_cancer.pdf


https://www.genome.gov/genetics-glossary/Chromatin


https://en.wikipedia.org/wiki/Mass_spectrometry#:~:text=Mass%20spectrometry%20(MS)%20is%20an,mass%2Dto%2Dcharge%20ratio.


Images:

https://www.flickr.com/photos/135558908@N04/50653501577/in/photolist-2kb5rh6-9gsMxq-KiinvV-8uLKvY-dxsFaq-bk42PS-22HcmbT-a3Xwxb-8qWGhj-nm7TGS-2eknUHg-rzwAKk-oQpGgT-5o66kM-e6dK6V-2kukEV9-UWdG1b-WaausU-7LzR9U-W23J6x-WaatbA-VCnAxA-UWfsFS-Bm9RGd-WaaqHQ-UZ6gbX-VCnyYy-VCnytA-VCp6FU-UZ6eRH-WdxMjB-UZ6e2B-VXGchs-TDkF8n-gHkeCk-5gYb7X-2jj4Pti-7LzR3S-xaFrRz-2ixyLMs-d1w1a9-gnZ1gz-uHzsug-Mtsp4n-dvTywo-nGH9aZ-eEPXa7-nGYqfY-mpgEMX-qzx5W1


https://pixabay.com/illustrations/man-dna-spiral-biology-merge-2125123/


What Did You Learn?

Questions:

1. Why is the role of epigenetics important to observe in cancer?


Previously it was thought that cancer was a purely genetic disease, caused by irreversible genetic mutations. However, it has become apparent that epigenetic changes are also important. Epigenetic changes in one cell can be spread to its daughter cells, so it is crucial to realize that negative changes could lead to a chain of events that cause tumor growth and invasion. Because these changes are reversible ones, knowing the extent to which epigenetic factors determine cancer progression, and the ways to stop the malignant changes from occurring, could be game changing in treatment of cancer.


2. What are some epigenetic changes in cancer that differ from normal cells?


DNA methylation is a marker for cancer, as global hypomethylation causes nuclear deformations and instability within chromosomes and genetic code. Genes expressed in tumors, as a result, may not be silenced and regulated through the naturally occurring methylation found in normal cells. Aside from a global decrease in DNA methylation, there is also an increase in methylation of specific CpG sites. Promoter regions are known to have hypermethylation leading to the inactivation of tumor-suppressive genes. Cancer progression becomes less regulated as tumor suppressor genes are silenced.


Histone modifications are another epigenetic change that eventually can interfere with normal nuclear processes and gene expression. Histones are a type of protein found within chromatin, the substance which makes up chromosomes. Methylation is one way that histones are modified, and its effects differ by the type of amino acid and position of the amino acid being modified. The modifications lead to differences that may cause cancerous behavior or genetic changes.


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