Epigenetics and Cancer

Epigenetics and Cancer

What is epigenetics and why is it important in cancer?

Epigenetics has become a widely used term. However, as researchers point out, despite its apparent popularity, the increased use of the term epigenetics has been probably more related to discrepancies in the definition. These inconsistencies in the definition and use of the term epigenetics lead to multiple meanings, trying to describe very different processes1. This lack of a clear definition has led to much confusion and a widespread misuse of the term epigenetics. 

That is why we want to start by addressing the meaning of the term epigenetics.

Etymology of Epigenetics

Greek prefix Epi- + Genetic

Epi – Word-forming element meaning “on, upon, above,” also “in addition to; toward, among.” 2

Genetic – From Greek genetikos from genesis “origin”; “pertaining to origins”3

Definition

There are many definitions of epigenetics, however a widely accepted one within the biology field is “the study of heritable and stable changes in gene expression that occur through alterations in the chromosome without alterations in the DNA sequence”4.

Going back to the etymology of the term, in epigenetics the prefix epi- means above and implies features that are “on top of” or “in addition to” the traditional genetic basis for inheritance. It can also be defined as on top of the basic DNA sequence5,6.

A good analogy to better understand this concept is thinking of accent marks on words. DNA are the words that make up the language and the modifications are the accent marks that change the way the words are read and the expression of the language. In epigenetics, the “marks” on the DNA change the way genes are expressed5.

But what does this mean? What are these epigenetic changes and how do they affect our genes?

Basically, epigenetics allows us a different interpretation of the cell, other than just looking at DNA or gene expression. As some researchers point out, the present definitions of epigenetics reflect that, although the DNA is essentially the same in all of an organism’s cells, patterns of gene expression differ greatly among different cell types, and these patterns can be inherited7.

So, we already know the structure of our DNA, the building blocks that make up our genes. And we know that almost every cell in our body has the same set of genes5,8. Then how can we explain how those genes are expressed so differently? Even when looking at identical twins that have the same genetic make-up, how can they be and look so different? 

Because any cell will have specialized epigenetic patterns. 

Epigenetic processes determine which genes are turned on or off and when that happens. DNA is like an instruction manual, but the genes still need specific instructions. The epigenetic processes give instructions to the cells to read different pages from the manual at distinct times and different circumstances8.

Although epigenetic mechanisms do not directly alter the DNA sequence, they can regulate gene expression through chemical modifications of DNA bases and changes to the chromosomal superstructure in which DNA is packaged9.  When a chemical compound binds to DNA, certain genes can be switched on or off, affecting which proteins are produced. 

Three different epigenetic mechanisms have been identified: DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing9.

• Histone modification

Histone proteins can suffer chemical alterations. When chemical compounds bind to histone proteins changing the formation of chromatin, the aggregation of chromatin results in the formation of a chromosome8,9. The chromatin of a chromosome exists as either loose (euchromatin) or dense (heterochromatin). The loose state is transcriptionally active because it allows transcription factors and enzymes to interact with the DNA, while the dense state is transcriptionally inactive, by preventing initiation of transcription. Hence, epigenetic modifications, by altering chromatin formation may contribute to facilitate gene expression in the open state or contrarily suppress gene expression in the closed state9. 

• DNA methylation 

DNA methylation is a mechanism of epigenetics associated with gene silencing. It occurs by the addition of a methyl (CH3) group to certain locations on the DNA. The methyl groups project into the major groove of DNA, and change the structure of DNA, inhibiting transcription, which often leads to modification of gene function (make genes more or less active) and altered gene expression (affecting protein production) 8,9,10. 

DNA methylation plays an important role in multiple biological processes such as, tissue-specific gene regulation, genomic imprinting, X chromosome inactivation, and is also associated with cancer development9,10.

• Non-coding RNA (ncRNA)-associated gene silencing 

Non-coding RNA sequences have shown to play a key role in the regulation of gene expression. This is the most recently elucidated epigenetic mechanism associated with gene silencing. 

As so well described by a 2021 paper, a “non-coding RNA (ncRNA) is a functional RNA molecule that is transcribed but not translated into proteins. Once regarded as waste of the genome, recent insight suggests the ncRNA molecules harbor a crucial role in epigenetic gene expression and likely account for the great difference in phenotype between species and within human populations despite such similarity in encoded proteins9.”

These epigenetic changes might be stable and last during the organism’s life, and some may even be passed on from one generation to the next – heritability – without a corresponding change in the genes or DNA8.

What is the significance of epigenetic modifications?

The epigenetic mechanisms described above are normal processes within cells and play a crucial role in the early life of the cells (especially stem cells and cells capable of turning into more specialized cells) since it is then that its development and specialization is determined8. 

However, such processes might also be initiated by environmental factors later in life, hence the enormous importance of the environment in the maintenance of health and disease development.

This influence of environmental epigenetic factors can be more easily identified when looking at identical (monozygotic) twins, who share the same genetic constitution – genotype – but express different observable traits – phenotype. These twins are often not that “identical”, since they have different anthropomorphic features (weight, height, etc.) and disease susceptibilities (for example, susceptibility to psychiatric diseases or cancer). While there might be several possible factors influencing this observable difference, a crucial one is epigenetic modifications11. 

A 2005 study showed exactly this; identical twins were found to be epigenetically indistinguishable during the early years of life, considering both DNA methylation and histone modifications, but older identical twins showed notable differences in these same epigenetic patterns, which leads to altered gene expression and the correspondent variable physical traits and disease susceptibility11. Therefore, knowing that identical twins share the same genetic background, the observable differences can be, at least partially, attributed to the exposure to different environmental factors8.

Factors influencing epigenetic modifications and health

As stated above, epigenetic processes are determinant in cell development and necessary for normal cell function. These mechanisms are especially important in genes where only one parental chromosome is expressed, and where DNA methylation is the process by which the other parental chromosome is silenced.

However, as people age, these mechanisms may also be caused or disrupted by environmental factors, such as; age, diet, smoking, psychological stress, pollutants, and disease state. Alteration of gene expression patterns driven by malfunctioning of epigenetic processes may induce many health conditions associated with genomic imprinting, namely autoimmune diseases and cancers9,12.

For example, considering DNA methylation, cancers have been found to “show marked hypermethylation of tumor suppressor genes and hypomethylation of proto-oncogenes”, both conditions contributing to tumor carcinogenesis9.

On the good side, and from a clinical perspective, if we know the normal pattern of DNA methylation in a healthy cell, and then analyze the methylation pattern in a cancer cell, we may be able to identify the modifications occurring and which genes can be affected5.

Important note for mothers and future mothers

Sensitivity to epigenetic changes may be greatest during the in-utero period. During this very delicate stage, critical windows are narrow, and the epigenetic profile of the fetus is being set and very vulnerable, due to the rapid formation and development13. Exposure to teratogens (an agent that causes malformation of an embryo or fetus), such as alcohol and cigarette smoke, may induce in utero epigenetic changes, and parents should be cautious and avoid these “man made” environmental factors 13,14. Evidence of this is a 2012 study that found smoking-related, subtle but stable methylation shifts in utero, which may explain the increased frequency of low birth weight infants born to women who smoke during pregnancy14.

Importance of Epigenetics in Cancer

You have probably heard that cancer is a genetic disease, and cancer genetics, indeed, have focused, for many years, in genetic mutations whose primary effect happens within cancer cell15. However, more recently the focus on genetics has changed and widened, thanks to the understanding of epigenetic events and the evidence that the epigenetic control of gene expression plays an important role in cancer development15.

To give you an overview of some of the main types of genes that play a role in cancer, we will shortly explain oncogenes and tumor suppressor genes.

Oncogenes

In the normal, unmutated state, these genes are called proto-oncogenes, and they are present in every cell of the human body. Proto-oncogenes play important roles in controlling cell division and cell death during growth and development. The problem arises when these genes are mutated or present in too many copies, leading to abnormal activation and uncontrolled cell division. When these proto-oncogenes are mutated and activated, they contribute to cancer development and are referred to as oncogenes. In short, when there are too many proto-oncogenes, or they become permanently activated (turned on), they can promote the development of cancer, through uncontrolled cell division and growth16,17,18.

Although this is a genetic event, very few cancers are caused by inherited mutations of proto-oncogenes that cause the oncogene to be activated. Contrarily, most genetic mutations in oncogenes, promoting cancer development, are acquired, not inherited. These genetic changes may result from errors on cell division and growth or from exposure to DNA damaging substances. These DNA damaging substances that may lead to cancer development are called carcinogenic, and include substances such as tobacco smoke, toxic chemicals or radiation16,17. 

DNA changes can vary greatly, affecting from one single unit of DNA to larger stretches of DNA17. But many cancer promoting changes do not occur at DNA level, or affect DNA sequence, and those are the epigenetic modifications. Epigenetic mechanisms may influence whether a gene is turned on or off, affecting gene expression and protein production (through messenger RNA production and concomitant translation into proteins), through chromosomal alterations, but not changing the DNA sequence17. 

Tumor suppressor genes

These are normal genes that slow down cell division, repair DNA mistakes, and regulate programmed cell (apoptosis) 16. Similarly to what happens with oncogenes, when tumor suppressor genes malfunction or are mutated, it can lead to uncontrolled cell division and growth and cancer promotion16. 

One example of a tumor suppressor gene is the TP53. The TP53 gene provides instructions for making a protein called tumor protein p53. This protein acts as a tumor suppressor, regulating cell division and preventing uncontrolled or rapid growth and proliferation. Abnormalities of the TP53 gene have been found in more than half of human cancers16,19. 

What is the difference between oncogenes and tumor suppressor genes?

• Oncogenes are the result of the activation, or turning on, of proto-oncogenes, resulting in cancer.
• Tumor suppressor genes cause cancer when inactivated or turned off.

Once again, most tumor suppressor gene mutations are acquired, not inherited. This is the case also for p53, whose acquired mutations appear in many human cancers16.

Conclusion

As referred to by many researchers, epigenetics is a very promising field of study. Epigenetic mechanisms open the door to the control of gene expression without changing the DNA sequence. This may allow for clinical interventions with increased safety and without the ethical concerns of DNA modification in humans9.

It is important to take home the notion we are not our genes, but the expression of our genes. Indeed, very few cancers are inheritably genetic, and even if you carry a “cancer” gene, this might be turned on or off by environmental factors. Even if you have been exposed to detrimental environmental factors, such as poor diet or smoking, you are not doomed, since most epigenetic modifications are reversible. Therefore, when considering cancer or any other lifestyle disease, in order to prevent and avoid recurrence, even if you have been exposed to a disease prone environment, if you change that environment, you can reverse those malfunctioning epigenetic changes and reverse disease.

With this in mind we invite you to read some of our articles on factors that are under your control and can help change your environment and the environment of your cells, into a healthier, cancer free one!

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REFERNCES

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