Manipulating tags on DNA without changing the underlying sequence triggers a chain of molecular events that may help prevent the spread of cancer, a new study by Indian scientists has revealed.
Development of cancer is a multistep process involving changes in several genes. Although the blueprint for cell’s life is kept in DNA for all events like growth, maturation, division, and even death, it is proteins that essentially do all the required work.
The new study shows epigenetics (changing activity of a DNA segment without changing sequence) anomalies could alter DNA instruction manuals for splicing that may lead to the synthesis of a particular type of mRNA and eventually proteins, in cancer cells.
In the study published in journal Proceedings of the National Academy of Sciences, Dr. Sanjeev Shukla's group at Indian Institute of Science Education and Research (IISER), Bhopal- has successfully identified a novel way to target glucose metabolism and thereby breast cancer cells by switching the alternative splicing of PKM gene.
According to the study, most of the cancer cells derive their energy from an energy production process called aerobic glycolysis that involves the transformation of glucose to lactate, when limited amounts of oxygen are available. Pyruvate kinase, an enzyme that catalyzes the last step of glycolysis seems to be an important regulator of this switch in the metabolism of glucose. Out of four isozymes of pyruvate kinase, isozymes M1 and M2 result from alternative splicing of transcripts coded by the PKM gene. Interestingly, the PKM2 alternative isoform is expressed by highly proliferating cells including cancer cells suggesting that regulation of PKM1/PKM2 ratio may hold the key to regulate cancer proliferation.
Researchers have discovered that the PKM2 specific exon inclusion is regulated by DNA methylation and a CTCF related protein BORIS (Brother of Regulator of Imprinted Sites) which preferentially binds to the PKM2-specific-methylated exon. As a result of this, splicing process gets altered in the case of cancer cells in such a way that instead of exon 9, exon 10 gets included when the pre-mRNA is spliced into mRNA.
“Our study suggests, we can potentially target DNA methylation to switch the cancer-specific splicing isoform to normal isoform and thereby inhibit the growth of cancer cells,” explained Dr. Shukla, who is a Wellcome Trust/DBT India Alliance Fellow. “DNA methylation or BORIS may serve as a potential target to inhibit the growth of cancer cells. As the epigenetic marks are reversible, they are an attractive target for cancer therapy,” he added.
Collaborators in this study, Dr. Rajendra K. Panday and Dr. Atul Samaiya from Bansal Hospital, Bhopal say “the new findings will help in the development of potential target for cancer therapy and will be useful in patient management in future.”
“As a therapeutic strategy, inhibiting the growth and accelerating the death rate of breast cancer cells may be possible by starving the cancer cells of glucose or by inhibiting or reversing aerobic glycolysis. Aerobic glycolysis confers a proliferative advantage to the cancer cells. The work of Dr. Shukla's group connects DNA methylation to alternative splicing and cell proliferation suggesting that epigenetic manipulation may provide a novel approach to dysregulate RNA processing and inhibit cancer proliferation,” says Dr. Sanjeev Galande, Scientist at IISER-Pune, who is not related to this study.
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