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Ten years ago, genome sequencing brought a big surprise: About half of human cancers are related to mutations in epigenetic regulatory factors, including lymphoma
.
Researchers at the University of Southern California and the University of North Carolina at Chapel Hill have recently developed a new drug-like molecule that can counteract the effects of mutations in epigenetic regulatory factors
.
This result was published in the "Cell Chemical Biology" magazine
How epigenetic regulators control gene activity
In healthy cells, epigenetic regulatory factors play a vital role: the activities of hundreds of genes are turned on and off in a carefully arranged sequence, guiding normal human development
.
As one of the epigenetic regulatory factors, EZH2 controls the transient inactivation of specific genes in order to allow immune cells to mature
.
However, the mutated EZH2 may continue to suppress these genes, thereby preventing the normal development of immune cells and eventually causing them to transform into malignant tumors
The good news is that unlike many other types of mutations, cancer-causing mutations in epigenetic regulatory factors are expected to be reversed by drugs
.
With this in mind, Junghyun L.
"Writer" and "Reader"
Suh and colleagues first considered the mechanism by which EZH2 suppresses genes
.
EZH2 acts as a "writer", marking which genes will be suppressed
Compared with the writer, the reader CBX8 seems to be equally important for the proliferation of cancer cells, but it is dispensable for healthy cells
.
This means that drugs that target readers will have fewer side effects on patients' healthy cells
In order to specifically target CBX8, the researchers first designed mouse stem cells so that they could easily screen a large number of drug-like molecules
.
These stem cells rely on CBX8 to read the mark left by EZH2, thereby inhibiting a gene that expresses green fluorescent protein (GFP)
Targeting "readers" to counteract mutations
Then, based on their knowledge of CBX8, the researchers performed multiple iterative analyses on drug-like molecules
.
They considered the complex protein structure of CBX and the way it binds to DNA and reads inhibitory marks
Co-corresponding author Oliver Bell, assistant professor at the Keck School of Medicine of the University of Southern California, said: "When we expose human lymphoma and colorectal cancer cells to newly synthesized drug-like molecules in the laboratory, the malignant cells stop proliferating and Began to behave more like healthy cells
.
"
Professor Stephen V.
Frye of the University of North Carolina at Chapel Hill added: “Our CBX8 targeting molecule is the strongest we have seen in blocking the function of the reader
.
This opens up opportunities for the exploration of related cancer therapies.
It has opened a path and enhanced our understanding of the epigenetic regulation of normal human development
.
"
###
Junghyun L.
Suh, Daniel Bsteh, et al.
Reprogramming CBX8-PRC1 function with a positive allosteric modulator.
Cell Chemical Biology, 2021; DOI: 10.
1016/j.
chembiol.
2021.
10.
003
