Changing the Face of Early Cancer Detection

Changing the Face of Early Cancer Detection: Better detection of PTMs could help cancer diagnostics

By: Alisha Desai

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The survival rate for individuals diagnosed with in the diagnostics and melanoma at the earliest stage of detection healthcare industry. is 99 percent. This survival rate drops to a Dr. Marcey Waters daunting 25 percent when the cancer is detected specifically studies how after spreading further throughout the body.1 Early methylation regulates detection could determine survival for the hundreds gene expression. of thousands of individuals that get diagnosed with Methylation is the skin cancer every year. The field of epigenetics has addition of a methyl played a significant role in establishing methods of group, CH3, to a early cancer diagnostics and UNC-Chapel Hill’s Dr. compound. CH3 is a Marcey Waters is one of the scientists pioneering this small organic molecule groundbreaking research. that is very prevalent in Figure 1: Image depicts DNA Epigenetics is the study of changes in an the body. When asked wrapped around histones, and organism caused by modified gene expression. Gene what drew Dr. Waters to then unwrapped, displaying the bonds which hold DNA together. expression describes the process of “turning [a gene] this field of research, she on or off.” . Every cell in the human body, whether it stated, “It’s remarkable that doing something as small is in the liver or the eye, contains an set of genetic as adding a methyl group on the right nitrogen can material. However, only specific genes are turned on turn on a protein-protein interaction that controls in certain cells allowing the liver and the eye to have gene expression.”2 Dr. Waters is particularly examining vastly different functions. The field of epigenetics is the methylation of lysine in histones, a type of protein new; in fact, researchers have only begun examining in DNA. Lysine is one of the amino acids that makes modified gene expressions within the past twenty up these histones. Dr. Waters is investigating lysine years. Nevertheless, it has quickly become clear that methylations by applying various biological and gene expression can cause severe diseases such as organic techniques. The lab is taking two approaches cancer; learning about these modifications and being to research these methylations: studying the able to reverse them could have significant effects proteins involved in methylation and using organic 20

chemistry to mimic the proteins. A solid foundation of understanding these methylations has emerged over the past decade. In the future, the lab will focus on engineering protein inhibitors. These inhibitors will regulate gene expression on the histones. Principles of organic chemistry are being applied to develop smaller molecules that are able to bind to the compounds of interest. Finding compounds with good binding affinity and selectivity has also been a major focus for the lab. Typically, antibodies, proteins used by the immune system, sense the lysine methylations. However, antibodies are expensive and creating them is a lengthy process which involves injecting rabbits with a compound and waiting for the rabbit’s body to create the proper antibodies. In addition, antibodies are very large and therefore have difficulty differentiating between smaller changes to the histone. Therefore, since methylations are very minor changes, the antibodies could have trouble detecting them. Dr. Waters also noted, “there are all these commercially available antibodies that have a large fraction of false positives and false negatives… they fail 25% of the time.”2 This posed an important question for the research group: is there a way we can use the existing reader proteins as sensors? The immediate answer was yes, but not nearly as well. Reader proteins have the natural selectivity to bind to methylated amino acids like lysine, and they are much cheaper and easier to make using typical biochemical tools. However, they are thought to have a much lower binding affinity compared to antibodies. Antibodies bind to methylated lysine one to ten thousand times tighter than reader proteins. Therefore, in order to use reader proteins as binding sensors, Dr. Waters and her team had to engineer them in a way to allow for a higher binding affinity. They have found success with engineering these reader proteins by introducing three mutations. These mutations enhanced the

Figure 2: Illustration demonstrates the improved efficiency of engineered reader protein compared to the selected antibody. protein’s binding ability twenty-five-fold. The Waters Lab have been pioneers in this niche of epigenetics. Many other researchers have used reader proteins to look for methylations, but Dr. Waters was one of the first to engineer the reader proteins to enhance their binding Dr. Marcey Waters, PhD ability thereby increasing their efficiency. When compared to a sample antibody, the newly engineered reader protein had a greater binding ability. In the past, the Waters Lab has focused specifically on creating engineered reader proteins for a particular lysine methylation; however, they are now hoping to apply this method to enhance detections of various other lysine methylations. This research is particularly important as it pertains to cancer diagnostics and treatment. When discussing potential applications of her research, Dr Waters stated, “anything that controls gene expression, if it is not regulated, will lead to disease. Cancer is one of the main diseases associated with methylations or lack of methylations.”2 Many studies have proven a link between deregulation of methylations and increases in certain types of cancer including melanoma.3 Increased methylations on various histones can contribute to an increased production of melanoma cells. In the future, Dr. Waters’ research will create more efficient detection methods for histone methylations that will be utilized in order to detect cancer sooner. This new method of detection could drastically increase patients’ odds of surviving cancer.

References

1. American Cancer Society. “Survival Rates for Melanoma Skin Cancer”. https://www.cancer.org/ cancer/melanoma-skin-cancer/detection-diagnosisstaging/survival-rates-for-melanoma-skin-cancer-bystage.html 2. Interview with Marcey Waters, PhD. 09/11/20. 3. Azevedo, H., Pessoa, G.C., de Luna Vitorino, F.N. et al. Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis. Clin Epigenet 12, 127 (2020). https://doi. org/10.1186/s13148-020-00910-9