Long Non-Coding RNA May be a Promising Therapeutic Target for Cancer 

Northwestern Medicine scientists have discovered that a specific long non-coding RNA activates oncogenic signaling pathways in prostate cancer cells and drives tumor progression, underscoring its potential as a therapeutic target, according to a recent study published in Nature Communications. 

Rendong Yang, PhD, associate professor of Urology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was co-corresponding author of the study.  

Long non-coding RNAs (lncRNAs) are a type of RNA with transcripts that contain more than 200 nucleotides and play a central role in regulating gene expression, most notably in cancer progression.  

While previous work has identified many cancer-associated lncRNAs, the mechanisms by which lncRNAs influence cancer progression have remained unknown due to lncRNAs’ cell type- and tissue-specific gene expression patterns.  

In the current study, the scientists aimed to uncover cellular interactions between super-enhancers — clusters of regulatory DNA elements that drive high levels of transcription — and lncRNAs by studying RNA sequencing data from patients with metastatic castration-resistant prostate cancer.  

Using a variety of transcriptomic techniques, the investigators identified a total of 1,344 lncRNAs. Of these lncRNAs, they discovered that an antisense lncRNA in the IGF1R locus, called IGF1R-AS1, demonstrated the strongest association with super-enhancers.  

Through computational analysis and gene knock-down experiments, the scientists also discovered that IGF1R-AS1 is expressed solely in tumor tissue and not in normal healthy tissue and is particularly overexpressed in prostate and lung cancer cells.  

Furthermore, they found that IGF1R-AS1 directly interacts with chromatin remodeling complexes that regulate chromatin structure and gene expression, as well as architectural proteins — a specialized class of proteins that shape the organization of the genome.  

This interaction promotes a chromatin loop between enhancers of the oncogene MYC and its promoter region, which causes MYC overexpression and tumor progression, according to Yang.  

“It seems that this lncRNA plays a central role in forming a loop between an enhancer and the MYC promoter at chromosome 8 to trigger the overexpression of MYC,” Yang said. “To our knowledge, this is the first time we have identified a lncRNA located on a different chromosome that regulates MYC expression through long-range chromatin interactions.”  

The findings suggest that IGF1R-AS1 helps steer the development of MYC-driven cancers, including prostate and lung cancers, and reveals a potential therapeutic target for MYC, which has previously remained undruggable.  

“This could be our way to target MYC by targeting the lncRNA, because the lncRNA seems to be a button to turn on MYC expression. If we can somehow target the lncRNA, then we could indirectly shut off the MYC signaling so that it won’t trigger the tumor growth. The lncRNA itself also has some prognostic potential because we test the lncRNA expression across multiple cancer types,” Yang said.  

Next steps for this work, according to Yang, will involve identifying other tumor-specific lncRNAs and determining how they influence oncogenic signaling pathways in other diseases.  

Qi Cao, PhD, the Anthony J. Schaeffer, MD, Professor of Urology, and Scott Dehm, PhD, professor of Laboratory Medicine and Pathology at the University of Minnesota Medical School, were co-corresponding authors of the study.   

Co-authors of the study include Qingshu Meng, PhD, research assistant professor of Urology; Abhirami Ramakrishnan, a student in the Driskill Program in Life Sciences (DGP); and Edward Schaeffer, MD, PhD, the chair and Harold Binstein Professor of Urology.  

This work was supported in part by grants from the National Institutes of Health (R01CA259388, R35GM142441, R01CA256741, R01CA278832, R01CA285684, R01CA300246, Prostate SPORE P50CA180995 Developmental Research Program, R01CA174777, R01CA270539, R01CA276269 and R35GM150941), the Department of Defense (W81XWH -21 – 1 – 0146, HT9425 -23 – 1 –0491, W81XWH -19 – 1 -0563 and W81XWH -20 – 1 -0504), the Prostate Cancer Foundation Young Investigator Award, the Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, the American Cancer Society Research Scholar grant RSG -21 -034 -01 –TBG, the Lung Cancer Research Foundation (992504), and the Windfeldt Cancer Research Award.