American biologists have discovered a gene mutation that leads to the development of cancer. The authors studied the new mechanism on the example of leukemia, but believe that it also works in other oncological diseases. The results of the study are published in the journal Nature.
Researchers from the University of North Carolina (UNC) at Chapel Hill and the UNC Lineberger Comprehensive Cancer Center have discovered a biophysical mechanism that activates certain genes that lead to the development of cancer.
They showed that a mutation combining two unrelated genes triggers a physical phase separation process similar to that which occurs when two immiscible liquids, such as oil and water, are combined. When the phases are separated, compartments are formed inside the cell nucleus — cells with different physical properties that can contribute to the development of cancer.
“Phase separation and its role in cancer development was the missing piece of the puzzle in understanding this disease,” study leader Dr. Greg Wang, associate professor of biochemistry, biophysics, and pharmacology at the UNC School of Medicine said in a press release from the Lineberger Center.
According to the authors, this discovery, linking the separation of phases with the formation of cancer, allows us to take a new look at the complex, multi-stage process that connects biology and physics.
To help decipher this process, the researchers conducted laboratory experiments on cancer cells carrying a common fused gene called NUP98-HOXA9. This abnormal fusion is found in the blood cells of patients who develop leukemia.
“Since similar gene mergers have been observed in other cancers, the mechanism we discovered may explain other types of cancer,” said Douglas Phanstiel, associate professor of cell biology and physiology at the UNC School of Medicine. — We believe that our findings will help create innovative methods to fight cancer cells.”
The proteins produced by NUP98-HOXA9 have unstructured regions known as internally disordered regions or IDRs. The role of IDRs has remained a mystery until now, but researchers have shown that IDRs promote liquid-liquid phase separation for NUP98-HOXA9 proteins when they reach critical concentrations in the nucleus, causing the NUP98-HOXA9 complex to become phased, or compartmentalized.
“Liquid-liquid phase separation changes the behavior of the NUP98-HOXA9 proteins, and causes them to bind much more strongly to the target genes,” explains first author Dr. Jeong Hyun Ahn, a research associate at UNC. “The DNA binding of the NUP98-HOXA9 proteins, when they are separated into phases, generates a unique pattern called a super-enhancer. Stronger binding of NUP98-HOXA9 proteins to DNA leads to the stronger activity of this factor, which is the basis for the formation of aggressive blood cancer.”
Theoretically, the authors believe, it is possible to create a drug that will destroy or dissolve the liquid droplets formed by NUP98-HOXA9 divided into phases.
“We hope to explore possible therapeutic agents that target phase separation, as we know that this process can also affect neurodegenerative diseases such as Alzheimer’s disease, where plaques that accumulate in the brain may be partially associated with liquid-liquid phase separation,” notes Wang.
So far, scientists have performed all the experiments in the laboratory, but they hope to soon test how the mechanism they discovered works on living organisms.