DoD grant awarded for investigating alternative polyadenylation in prostate cancer

A team led by Dr. Eddie Imada, assistant professor of research in pathology and laboratory medicine, has been awarded a three-year, $1.5 million United States Department of Defense grant for research on a cellular process called alternative polyadenylation and its role in prostate cancer.

The grant was awarded under DoD’s long-running Prostate Cancer Research Program, a Congressionally-directed medical research funding project aimed at improving prostate cancer prevention, detection and patient care. Thousands of current and former servicemen are diagnosed with, and die of, prostate cancer every year.

At first glance, polyadenylation isn’t an obvious culprit in cancer. It is an evolutionarily ancient and routine process that adds a tail of RNA nucleotide “letters”—all of them adenosines, represented by the letter “A” in the genetic code—to one end of a gene’s newly made RNA transcript. This polyA tail and other routine modifications turn the transcript into a messenger RNA (mRNA). Scientists know that polyadenylation increases the stability of the mRNA and helps it exit the cell nucleus so it can be translated into a protein in the cytoplasm.

On the other hand, polyadenylation is not a straightforward process: For about two-thirds of human genes, the place where the raw RNA transcript is trimmed and polyadenylated – known as polyadenylation sites – sometimes differs resulting in what is termed alternative polyadenylation. This “alternative polyadenylation” can lead to a host of changes including greater or lesser production of the protein encoded by the gene, or even different versions of the protein. In some cases that appears to be a normal, healthy way of fine-tuning various cell processes, including cell division and cell maturation. In other cases, alternative polyadenylation seems dysfunctional; it has been linked to multiple diseases including cancers.

Dr. Imada says his project may be the first in-depth, genome-wide exploration of alternative polyadenylation’s role in prostate cancer. He and his team will use computational analysis of RNA sequences from healthy individuals and from patient tumor samples to see how changes in polyadenylation site usage affect prostate cancer progression and treatment response.

Potential payoffs of the research include uncovering new molecular targets that can lead to new treatments for prostate cancer—which often becomes resistant to current treatments—as well as better ways of enhancing therapy selection for existing treatments such as immunotherapies.

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