A decade ago, genome sequencing revealed a big surprise: about 50% of human cancers are linked to mutations in so-called epigenetic regulators, which control the activity of of genes.
Medical researchers have now developed a new drug-like molecule that can counteract the effects of mutated epigenetic regulators, which are known to lead to several types of cancer including cancer. lymph nodes.
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In a new study in the Journal of Cell Chemical Biology, a team of scientists led by Oliver Bell from the University of Southern California and Stephen V. Frye from the University of North Carolina at Chapel Hill have developed a new drug-like molecule. may counteract the effects of mutated epigenetic regulators, which are known to drive several types of cancer including lymphoma.
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HOW EPIGENIC REGULATORS CONTROL GENE ACTIVITY
In healthy cells, epigenetic regulators play an essential role: turning on and off the activity of hundreds of genes in precisely ordered sequences that direct normal human development.
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One of these epigenetic regulators, EZH2, controls transient gene inactivation to allow immune cells to mature. However, mutant EZH2 can cause persistent suppression of these genes, thereby preventing immune cells from developing normally and ultimately leading to their transformation into cancerous malignancies.
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The good news is that in contrast to many other types of mutations, cancer-causing mutations in epigenetic regulators are reversible with drugs. With this in mind, lead author Junghyun L. Suh and team designed a drug-like molecule to reverse oncogene repression by EZH2.
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ROLE OF "THE WRITER" AND " THE READER"
Suh and her colleagues began by looking at the mechanism by which EZH2 controls gene repression. EZH2 acts as a "writer" marking which genes will be repressed. A second epigenetic regulator called CBX8 acts as a "reader" that interprets these suppressive signals and recruits additional regulatory machinery that actually turns off the genes.
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Compared to the writer, the CBX8 reader appears to be equally important for cancer cell proliferation, but no more important for the function of healthy cells. This means that drugs targeting the reader are expected to have fewer toxic side effects on healthy cells in the patient's body.
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To specifically target CBX8, the researchers first engineered mouse stem cells so they could easily screen a large number of drug-like molecules. These engineered stem cells rely on CBX8 to read marks deposited by EZH2 to inhibit a gene that produces a visible green fluorescent protein (GFP). If stem cells show activation that produces green light, scientists know then a drug-like molecule has successfully blocked CBX8 from reading the repression signals.
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TARGETING "READERS" TO FIGHT AGAINST MUTATION
The researchers then broke down their knowledge of CBX8 into several iterations of drug-like molecules that target this specific reader. They took into account CBX's complex protein structure, as well as how it binds to DNA and reads inhibition signals. Once they succeeded in synthesizing a potent molecule that worked well in engineered mouse cells, they turned to testing on human cancer cells.
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"When we exposed human lymphoma and colorectal cancer cells to our newly synthesized drug-like molecule in the laboratory, the malignant cells stopped proliferating and began to function. function like healthy cells," said Oliver Bell, an assistant professor of biochemistry and molecular medicine, stem cell biology and regenerative medicine at the Keck School of Medicine of USC, and a member of the Cancer Center. said USC Norris Comprehensive Letter, co-author of the study.
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"Our CBX8-targeting molecule has the most potent effect we have seen in terms of blocking reader function," said co-author Stephen V. Frye, the Fred Eshelman professor emeritus and fellow added director of the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina at Chapel Hill. "This opens an avenue for discovering relevant cancer therapies, as well as improving our understanding of epigenetic regulation in normal human development."
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Refferals:
Junghyun L. Suh, Daniel Bsteh, Bryce Hart, Yibo Si, Tyler M. Weaver, Carina Pribitzer, Roy Lau, Shivani Soni, Heather Ogana, Justin M. Rectenwald, Jacqueline L. Norris, Stephanie H. Cholensky, Cari Sagum, Jessica D. Umana, Dongxu Li, Brian Hardy, Mark T. Bedford, Shannon M. Mumenthaler, Heinz-Josef Lenz, Yong-Mi Kim, Gang Greg Wang, Ken H. Pearce, Lindsey I. James, Dmitri B. Kireev, Catherine A. Musselman, Stephen V. Frye, Oliver Bell. Reprogramming CBX8-PRC1 function with a positive allosteric modulator. Cell Chemical Biology, 2021; DOI: 10.1016/j.chembiol.2021.10.003
Translator: Hoàng Hiệp – Phacogen Institute of Technology,
(PhD in Biotechnology - UST University, Korea)
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Source of article:
https://www.sciencedaily.com/releases/2021/10/211029103124.htm
