Epigenetics in the Fight against Cancer

All of biology lives and dies by four letters: A, T, C, and G — the components of DNA. Our functions and physicalities, our organs, blood and bones, all reduce to this one cardinal script.

But in this intricate system, even the smallest changes can trigger genetic disaster. Until recently, doctors and researchers focused on small, permanent changes, called mutations, in the DNA sequence as the main instigator of some diseases, like cancer. But researchers are finding that many illnesses arise from more than just genetic mishaps. They’re finding that changes on the surface of the DNA, rather than in the DNA sequence itself, increasingly affect the onset and subsequent treatment of the disease.

The idea of DNA surface changes has sparked a discussion about the very way scientists study cancer, leading one researcher to ask a novel, yet critical question: Is there an off button?

The emerging field is known as epigenetics. Epi (meaning over, outside of, or around) indicates that the modifications to the DNA do not take place in the sequence itself, but rather, as additions to chromosomes (compacted molecular sticks that contain DNA) or the proteins that help make them.

Epigenetics research is based in the idea that what we breathe, eat, or are simply exposed to can reprogram gene expression and change how physical traits manifest in our bodies. It’s not exactly “you are what you eat,” but researchers have made strong, and in some cases undeniable, connections between environment and disease. The link between smoking and lung cancer is a prime example: smoking not only changes the sequence of DNA itself, but also makes changes outside the DNA that influence how it’s expressed in the lung, which contributes to uncontrolled cell growth and tumors.

“Traditionally, most researchers look at the genetic effects and only treat the symptoms of the mutation,” says Liang Gangning, associate professor of research at the University of Southern California’s Keck School of Medicine. But treating the symptoms doesn’t necessarily treat the cause, he says.

Sibaji Sarkar, an instructor at Boston University’s School of Medicine, centers his research on exactly that idea, focusing on two main epigenetic changes that he thinks are linked to cancer onset and relapse. Both involve chemical additions that alter large scale DNA expression. Once bonded to the chromosome or protein, the chemical acts as a switch that shifts how the DNA gets expressed as physical characteristics.

Part of Sarkar’s research explores the concept that cancer mimics a natural process in our bodies called epigenetic differentiation. Though it sounds daunting, this process is a normal, and vital, part of how humans develop various tissue types. The lungs and liver, for example, comprise cells that all contain the exact same DNA, yet carry out two different functions. Different snippets of DNA called genes regulate different parts of the body, based on their activation patterns. For example, the genes that control lung function are active in the lungs, but not the liver, and the genes that control liver function are active in the liver, but not the lungs. It’s the changes outside the DNA sequence that control activation of these genes. Sarkar thinks this process mirrors how normal cells get changed, or activated, into cancerous ones.

Of course, epigenetic changes alone don’t cause cancer. Cancer progression is an enormously complex mechanism involving both DNA mutation and epigenetic changes. On the genetic side, if the DNA sequence becomes mutated, it sends out a message that’s inconsistent with the original molecular blueprint. RNA, DNA’s sister molecule, translates the DNA’s message into proteins, but if the DNA is mutated the proteins come out defective.

Sarkar compares the mutation process to the rankings of the military. He compares the DNA to a general who devises a strategy, the RNA to the lieutenant who relays the message, and proteins to the troops that fight and do the actual work. But mutated DNA compromises the genetic strategy, skewing the message, which leaves the protein troops unable to properly do their job. Depending on the protein, that means uncontrolled cell growth.

Flawed DNA, however, is only part of what causes cancer. On the epigenetic side, a process that adds chemicals to the DNA, known as methylation, attracts the most attention. During methylation, a string of carbons binds onto a section of DNA and prevents the cell from reading the gene’s instructions. Our cells contain genes called “tumor suppressors” which control cell growth. But methylation of the tumor suppressor gene interferes with its purpose. As a result, cells grow more than they should, which can lead to tumors.

Depending on what region of the DNA it affects, methylation can elicit a huge range of responses. But these changes aren’t necessarily permanent: the carbons can detach from the DNA naturally. This reversibility gives researchers like Sarkar and Gangning a new angle in developing drugs for cancer. These drugs aim to reverse or stop the methylation from impeding the proper function of the cancer-fighting genes by binding to and blocking the site on which methyl groups dock. In May 2014, Sarkar suggested the possibility of a cancer “on-off switch,” the idea that, if demethylated, silenced tumor suppressor genes could turn on again and stop tumor growth, and even future relapse.

Four months later, Gangning and his colleagues found that an epigenetic drug, called 5-Aza-CdR, did indeed reactivate some tumor suppressor genes by removing the methylation. Without the suppressive methylation, the genes can recover its original purpose—suppressing tumors.

Epigenetics and cancer researchers like Sarkar and Gangning don’t aim to replace radiation and chemotherapy with epigenetic drugs. They see it as a supplement. The epigenetic drugs work synergistically to increase potency of the traditional treatments and decrease the rate of relapse.

“These epigenetic drugs are fine adjustments to the treatments we have currently — fine but extremely important,” says Sarkar.

The FDA approved a handful of epigenetic drugs for some end-stage cancer therapies. But the drugs are not yet widespread in clinical recommendations, mostly because they are non-specific and affect the genome as a whole. That is, instead of just demethylating the tumor suppressor genes, the drug has the potential to demethylate any gene, at random. This concerns many doctors because it can lead to other serious genomic complications.

Currently, the National Health Institute is pushing to develop more specific ways to target just the cancerous cells for demethylation. Other epigenetic studies use animal models to explore treatment time frames, as well as decide the best technique to administer therapies.

“Cancer is very complex, and to totally eradicate it is equally as complex. You have to cover all the bases,” says Sarkar. “It’s not just DNA changes; it’s changes on the DNA too, and that’s why these [epigenetic] drugs are necessary.”