Scientists from the Massachusetts Institute of Technology (MIT) in Boston have identified the mechanism by which a specific protein called PRMT5 drives the growth of glioblastoma tumors.
What is more, by blocking this mechanism with a class of existing drugs, they were able to arrest glioblastoma tumor growth in mice.
Study leader Christian Braun, who was a postdoctoral student at MIT at the time of the research, and colleagues recently published their findings in the journal Cancer Cell.
Glioblastoma – also referred to as glioblastoma multiforme – is a type of malignant brain tumor that forms from star-shaped glial cells called astrocytes.
According to the American Brain Tumor Association, almost 80,000 new cases of primary brain tumors are expected to be diagnosed in the United States this year. Of these, glioblastoma will account for around 14.9 percent.
While glioblastomas are not the most common brain tumor, they are the deadliest; median survival is just 14.6 months after a glioblastoma diagnosis, if a patient is treated with chemotherapy and radiotherapy.
As such, there is a desperate need to identify new therapies to prevent and treat glioblastoma. Braun and colleagues believe that their study findings could help to reach this goal.
PRMT5 and gene splicing
In previous research, Braun and his colleague Monica Stanciu, of the Department of Biology at MIT, identified PRMT5 as a possible driver of glioblastoma tumors, but the precise mechanisms by which the protein does so was unclear.
The findings indicated that PRMT5 might be involved in a unique form of “gene splicing” that fuels the growth of glioblastomas.
The researchers explain that gene splicing is a process in which sections of messenger RNA (mRNA) called introns are “cut” from mRNA strands, as they are no longer needed once genetic information has been conveyed to mRNA.
Later research revealed that around one to three “detained introns” persist in around 10 to 15 percent of human mRNA strands, and these remaining introns prevent mRNA molecules from leaving the cell nucleus.
“What we think is that these strands are basically an mRNA reservoir,” says Braun, who is now based at the Ludwig Maximilian University of Munich in Germany. “You have these unproductive isoforms sitting in the nucleus, and the only thing that keeps them from being translated is that one intron.”
In their latest study, as hypothesized, the researchers found that PRMT5 plays a crucial part in the unique gene splicing process; they suggest that brain stem cells have high levels of PRMT5, which they use to ensure effective splicing and greater expression of genes related to cell proliferation, or growth and division.
“As the cells move toward their mature state, PRMT5 levels drop, detained intron levels rise, and those messenger RNAs associated with proliferation get stuck in the nucleus,” explains study co-author Jacqueline Lees, of The David H. Koch Institute for Integrative Cancer Research at MIT.
They explain that in cancerous brain cells, levels of PRMT5 are increased once again, which, in turn, activates the unique gene splicing process and encourages the cancer cells to grow out of control.
Halting glioblastoma growth in mice
The researchers further confirmed their findings in human glioblastoma cells. When they inhibited PRMT5 – which prevents the production of the PRMT5 protein – in tumor cells, they found that cell growth and division was halted.
The researchers were also able to stop the growth of glioblastoma tumors in mouse models by treating them with PRMT5 inhibitors.
Commenting on the team’s findings, Omar Abdel-Wahab, of the Memorial Sloan Kettering Cancer Center in New York – who was not involved in the research – says, “PRMT5 has a lot of roles, and until now, it has not been clear what is the pathway that is really important for its contributions to cancer.”
“What they have found,” he adds, “is that one of the key contributions is in this RNA splicing mechanism, and furthermore, when RNA splicing is disrupted, that key pathway is disabled.”
Additionally, the study identified a biomarker that the researchers say could be used to identify patients who are likely to respond well to treatment with PRMT5 inhibitors.
This study not only sheds light on the underlying causes of glioblastoma, but it may also open the door to new prevention and treatment strategies for this deadly cancer.