This post was written by our guest blogger Janelle Weaver, Ph.D.
Eukaryotic cells consist of thousands of RNA molecules that do not get translated into proteins. These noncoding RNAs can be classified as long or small, depending on whether they consist of greater or fewer than 200 nucleotides. Scientists have characterized how small noncoding RNAs regulate gene activity, but until recently, they frequently dismissed long noncoding RNAs as non-functional noise. Over the past few years, more and more research has shown that long noncoding RNAs actually regulate normal cellular development and may contribute to a range of diseases, from Alzheimer’s to cancer.
A few years ago, Sanford-Burnham researchers discovered that a long noncoding RNA called SPRY4-IT1 is more abundant in cancerous skin cells than in normal skin cells, and that it promotes cancer-cell survival and growth. In a study published March 26 in Oncotarget, the researchers now report that SPRY4-IT1 plays an important role in regulating lipid metabolism in cancerous skin cells. The findings suggest that therapeutic inhibition of this molecule could trigger changes in lipid metabolism that are drastic enough to kill cancer cells.
“Since metabolic rewiring of a cell has become an established requirement for transformation processes such as cancer, this offers us a new avenue to explore both diagnostic markers for cancer detection and therapeutic targets for treatment,” said Joseph Mazar, Ph.D., a research scientist at Sanford-Burnham and first author of the paper.
Stymie SPRY, lipids go awry
In the new study, the researchers identified SPRY4-IT1’s major binding partner: an enzyme called lipin 2, which is involved in normal fat-tissue development and may also influence human lipid metabolism. When the researchers reduced SPRY4-IT1 levels in cancerous human skin cells, levels of the lipin-2 protein increased and there were significant changes in the abundance of many lipids in these cells. Taken together, these recent studies suggest that a drug that inhibits SPRY4-IT1 could kill cancer cells by throwing lipid metabolism off balance.
“Our results are the first to demonstrate a role for a long noncoding RNA in lipid metabolism in melanoma cells, and collectively, the data support the notion that SPRY4-IT1 may play a critical role in inducing skin cancer,” said senior study author Ranjan J. Perera, Ph.D., scientific director of the Analytical Genomics and Bioinformatics Core facilities and associate professor in the Metabolic Disease Program at Sanford-Burnham. “Our findings challenge scientists to recognize the importance of long-neglected noncoding RNAs and to look at melanoma from a different angle.”
Perera and his team are continuing to explore the role of SPRY4-IT1 and lipid metabolism in skin cancer as well as prostate-cancer biology. Specifically, they plan to investigate how SPRY4-IT1 regulates lipin 2 and downstream lipids. On the clinical side, they have found that SPRY4-IT1 can be used as a molecular marker to identify cancer in various types of tissues from patient biopsies, and now they are taking advantage of the Histology and Cellular Imaging Core facilities at Sanford-Burnham and Florida Hospital to validate the diagnostic use of this molecule in a large-scale study. The research team believes that in near future, long noncoding RNAs may serve as next-generation diagnostic markers and therapeutic targets for many diseases including variety of cancers.