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Two Small RNAs, Often Missing from Cancer Cells, May Suppress Tumors

December 14, 2015, by NCI Staff

RAS heart

The structure of the KRAS protein is visible in this artistic rendering.

Credit: National Cancer Institute

Researchers have discovered an unexpected link between two small RNAs that are frequently missing from cancer cells and the family of RAS genes, which are commonly mutated in cancer.

The RNA molecules—small nucleolar RNAs, or snoRNAs—may help suppress tumors by inhibiting the cancer-promoting activities of RAS proteins, according to the researchers. In the absence of these snoRNAs, RAS proteins may become “hyperactive,” producing continuous signals that promote cell growth.

Paul Khavari, M.D., Ph.D., of the Stanford University School of Medicine and his colleagues reported their findings about snoRNAs and RAS in Nature Genetics on November 23.

Roughly one-third of all cancers involve mutant forms of RAS proteins. Understanding more about what regulates these mutant proteins could lead to new strategies for treating or even preventing these cancers.

Testing a Role for snoRNAs in Cancer

Researchers have known for some time that snoRNAs regulate basic cellular activities, but recent evidence has suggested that they may also play a role in cancer. To explore this idea further, study coauthor Zurab Siprashvili, Ph.D., and his colleagues analyzed data on more than 5,000 participants in The Cancer Genome Atlas (TCGA) who had any of 21 types of cancer.

The investigators compared snoRNAs in the tumor and normal genomes from each participant. This analysis revealed that two snoRNAs, called SNORD50A and SNORD50B, were missing in at least 10 percent of 12 of the 21 types of cancer tested, including skin, ovarian, liver, lung, and breast cancer.

In addition, patients whose tumors lacked these RNAs tended to have worse outcomes than patients whose tumors had them.

Other snoRNAs normally act by binding to proteins. To understand how the absence of SNORD50A and SNORD50B might be affecting cancer cells, the researchers next looked for cancer-relevant proteins that bind to these snoRNAs. The analysis showed that the RNAs may bind to the KRAS protein and suppress the cancer-promoting activities of the mutant KRAS protein.

This idea was supported by additional experiments showing that human melanoma and lung cancer cells that were missing SNORD50A and SNORD50B divided more quickly than similar cells that had them.

Exploring Mechanisms of Tumor Suppression

Next, the researchers conducted experiments to learn how these two snoRNAs might suppress RAS activity. They found that when SNORD50A and SNORD50B bind to KRAS, this inhibits the protein’s ability to be modified by an enzyme called farnesyltransferase. Modification of RAS proteins by this enzyme is necessary for them to have full activity.

Based on their experiments, the researchers concluded that SNORD50A and SNORD50B are necessary for KRAS to respond appropriately to external signals. So, when these snoRNAs are missing, KRAS may become hyperactive.

“The discovery that RAS is an RNA-binding protein and that RAS-binding RNAs can regulate the function of RAS proteins opens the way for studies designed to exploit this observation therapeutically,” said Dr. Khavari. He cautioned, however, that much work needs to be done to make that happen, including an analysis of the three-dimensional structure of these interactions, as well as studies to identify the full spectrum of RNAs that bind RAS proteins.

“The Vast Richness of the TCGA Project”

The Stanford team used TCGA data in much the same way as other researchers, though the study’s focus on small RNAs that may play a role in regulating genes was not typical, observed Jean-Claude Zenklusen, Ph.D., of NCI’s Center for Cancer Genomics and the director of TCGA.

“We know that TCGA data has reams of information on regulatory regions of the genome that we have not explored,” said Dr. Zenklusen. “It is great to see that the community is using the data, as the intent of the program was to be a resource for all to exploit. This is another example of the vast richness of the TCGA project.”

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