Role of the macro lncRNA KCNQ1OT1 in embryonal rhabdomyosarcoma tumorigenesis
Embryonal rhabdomyosarcoma (ERMS) is a soft tissue cancer with features of skeletal muscle, and the most common soft tissue connective cancer of childhood. While the medical community has made great strides in improving care and cure for children with ERMS, there remains a group of children with high-risk disease who only survive their cancer about one third of the time. To develop new treatments for these children, it is important to understand what mutations their ERMS tumors carry. However, some ERMS tumors don't carry any abnormalities in their protein-coding genes, only in genes that code for very long, string-like RNAs (RNAs are related to DNA, but are more fragile). One of these mysterious string-liked RNAs is called KCNQ1OT1.
Project Goal: In this work, we propose to understand how KCNQ1OT1 contributes to ERMS tumor formation, what genetic programs KCNQ1OT1 triggers, and how KCNQ1OT1 can be targeted therapeutically. Our long-term goal is to find a way for every child with ERMS, regardless of the mutations or abnormalities in their tumors, to be able to have a medicine to improve their chances of survival.
Project Update 2023: The string-like RNA that we are studying called KCNQ1OT1 (abbreviated OT1) continues to be a mysterious and challenging molecule! It is very long – the longest RNA that we have every worked with – and probably has multiple ways of controlling genes in ERMS. To summarize, we have found that different ERMS human cell lines have different levels of OT1 and that ERMS cells resist it when we try to get rid of OT1. We have used a DNA editing method to inactivate OT1 and isolated single cells to see how they respond to this. We have also discovered some interesting things about OT1, including that it is evolutionarily conserved, that it has subdomains that are expressed at different levels and are predicted to bind DNA with different strengths, and that it may regulate its own expression. We have tested many new ways of targeting OT1 therapeutically and have found two ways that make ERMS cells stop in their tracks! We have trained several scientists including undergraduates and medical students during the course of this project and are happy to have gotten the word out about the importance of studying these long noncoding RNAs in childhood cancer. We are now joining forces with biochemist experts in RNA to identify regions of OT1 that might be blocked by other newer medicines.
