Length of some regions of messenger RNA plays key role in regulating gene expression, cancer growth
- Role revealed for little-known process known as alternative polyadenylation
- First large-scale single-cancer analysis of alternative polyadenylation events
- Changes to length of certain RNA segments can be key prognostic indicator
BUFFALO, N.Y.— Roswell Park Comprehensive Cancer Center researchers conducting the first large-scale analysis of a gene regulatory mechanism that, when altered, can lead to cancerous growth have found compelling evidence of the role it plays in the development of pancreatic cancer. They share these new findings in an article in the journal Genome Research.
Led by Michael Feigin, PhD, Assistant Professor of Oncology in the Department of Pharmacology and Therapeutics, the team studied a largely unexplored mechanism called alternative polyadenylation that recently has been found to play a significant role in regulating the expression of genes — particularly oncogenes, or genes known to be associated with cancer — in cells.
Oncogenes’ impact on cells is determined by how much protein they produce. The information encoded is transcribed to form a messenger RNA molecule, or mRNA, that when translated forms the protein.
Dr. Feigin, postdoctoral fellow Dr. Swati Venkat and colleagues set out to study what happens to the encoded information that doesn’t get translated, a phenomenon that, Dr. Feigin says, “remains completely unexplored in the context of pancreatic cancer and can provide understanding of how we target oncogenes that drive this debilitating disease.”
The length of this sequence of information at the end of a molecule, known as a 3 prime untranslated region or 3’ UTR, has been shown to influence the amount of protein produced: much shorter lengths cause increased protein production, leading to cancerous growth.
The team mined data from tissues from hundreds of people with pancreatic cancer as well as normal pancreas samples, searching for oncogenes that showed difference in 3’ UTR lengths between cancer and normal conditions.
“We found widespread, recurrently shorter 3’ UTR lengths of multiple oncogenes in pancreatic cancer patients,” says Dr. Venkat, first author on the new study. “This shorter length significantly increased gene expression of known pancreatic cancer oncogenes.”
The team also discovered a novel growth-promoting gene called casein kinase 1 alpha, whose mRNA exhibits a shorter 3’ UTR length in cancer cells that drives its increased expression and promotes cell growth.
“We conclude that 3’ UTR length changes drive widespread oncogene dysregulation in pancreatic cancer,” Dr. Feigin says. “Our next step will be to unravel the protein machinery that regulates these length changes and target these proteins to explore possible therapeutic avenues.”
The study represents the first large-scale analysis of alternative polyadenylation events ever performed within a single cancer type.
This work was supported in part by funding from the National Cancer Institute (project nos. P30CA016056 and R25CA181003) and U.S. Department of Defense (award no. W81XWH-18-1-0134), and by donations to Roswell Park.
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Annie Deck-Miller, Senior Media Relations Manager