New research is finding that different types of ribonucleic acids (RNAs) that do not encode protein are key players in cancer.1 One specialized RNA research group has coalesced at MUSC and is finding that these so-called regulatory RNAs can keep cancer in check or promote its development, depending on the presence of other pro-tumor molecules.
Before the human genome project, geneticists predicted that humans would have at least 100,000 different messenger RNAs, the type that encode proteins, within their DNA. There would have to be this many, they reasoned, to account for all the genetic variability observed in humans. But in 2012, the human genome project revealed that the number of protein-coding RNAs are less than a third of that predicted. What then could account for all the differences in human health and disease? The genome project revealed that non-coding RNAs, previously thought to be mere cellular junk, provide extra layers of regulation in our genes.
Philip H. Howe, Ph.D., the Hans & Helen Koebig Endowed Chair in Oncology and chair of the MUSC Department of Biochemistry & Molecular Biology, is an expert on RNA and the inflammatory molecule TGF-beta. Howe studies the functions of long non-coding RNAs (lncRNA) in cancer development. He and cell cycle and microRNA expert J. Alan Diehl, Ph.D., SmartState® Endowed Chair in Lipidomics & Pathobiology and associate director of basic sciences at the MUSC Hollings Cancer Center, recently embarked on a project involving both of their RNA types of interest. In their work, published in Nature Cell Biology in September 2017, they deciphered an interaction between different types of RNA that enables cancer cells to encourage their own growth.2
Howe and Diehl pondered a natural phenomenon during which DNA is converted to lncRNA instead of its normal protein-coding form. They found that TGF-beta released by cancer cells causes normal cells to make more lncRNA instead of the protein-coding form. When this happens, the lncRNA becomes a pro-tumor molecule. It soaks up a microRNA that usually discourages cancer growth, allowing normal epithelial cells to take on the features of cancer cells. The researchers confirmed that this process contributes to breast and lung cancer, thereby providing a new understanding of how cancer cells rid normal cells of healthy RNA to make way for RNA that encourages tumor growth.
There are dozens of different types of RNAs, each with distinct regulatory functions, that tweak the concentration of messenger RNAs through degradation, gene silencing or interfering with transcription.3 Howe recently recruited other young RNA experts to the department to reach the larger goal of building a team to understand the roles of these diverse RNAs in cancer. Among them are Vamsi Gangaraju, Ph.D., assistant professor, trained at Yale University, who studies how heat shock proteins and piwi-piRNA relate, and Viswamathan Palanisamy, Ph.D., associate professor, trained at the National Institutes of Dental and Craniofacial Research, who studies the roles of various RNA-binding proteins in oral cancer progression. Howe also recently brought in Je-Hyun Yoon, Ph.D., assistant professor, trained at the National Institute on Aging, to study the function of RNA-binding proteins. The group also started a collaboration with oral cancer researcher Andrew Jakymiw, Ph.D., assistant professor in the MUSC College of Dental Medicine, who has R21 funding to build delivery systems for silencer RNAs targeted to head and neck tumors.
This group of investigators has been working collaboratively for over two years to acquire the technology to discover and characterize these RNA species and their binding partners. This research effort has been supported by a pilot award from Hollings to foster team science, and in the upcoming year the group plans to submit a program project grant (PPG) to the National Cancer Institute. Their focus is to determine how these RNAs and their binding partners regulate the late stages of tumor progression, namely metastasis. “Metastasis, or the spread of cancer from a primary site to other tissues and organs, accounts for over 90 percent of cancer-related mortalities, yet it is probably the least understood process of cancer progression,” says Howe. “To better understand it, we need to find each RNA’s functional significance and mechanism of action. Then, long term, we need to consider whether these could be therapeutic targets.”
1 Batista, PJ, et al. Cell. 2013;152:1298–1307.
2 Grelet S, et al. Nat Cell Biol. 2017;19(9):1105-15. doi: 10.1038/ncb3595.
3 Morris KV & Mattick JS. Nat Rev Genetics. 2014;15:423-37. doi: 10.1038/nrg3722.