Bold claim: A cancer-related protein is connected to a key RNA modification, revealing new angles for prostate cancer treatment. A Northwestern Medicine study, published in the Journal of Clinical Investigation, uncovers a link between EZH2 — a protein long known for guiding gene regulation — and m6A, the most prevalent RNA modification in humans. This modification acts like a molecular switch that governs gene expression and protein production. While m6A has been associated with cancer progression, the precise mechanisms controlling it were not fully understood until now.
Lead author Yang Yi, PhD, an assistant professor of Urology, explains that this work advances the idea that different epigenetic regulatory systems may interact in meaningful ways. The study set out to explore how EZH2 could promote cancer by influencing the m6A modification.
In prostate cancer cells, the researchers observed that EZH2 does more than modify histone H3. It also stabilizes FOXA1, which in turn boosts the activity of YTHDF1, an m6A reader protein. This triggers a cascade in which YTHDF1 elevates the production of METTL14 and WTAP — two enzymes that write m6A marks on RNA — resulting in higher m6A levels in prostate cancer cells. Higher m6A levels then support cancer cell growth and survival, Yi notes.
When EZH2’s enzymatic activity was inhibited, the entire pathway was disrupted, leading to reduced protein production and slower cancer cell growth. Notably, combining an EZH2-targeting drug with an m6A inhibitor produced a substantial decrease in tumor growth in laboratory models of prostate cancer, indicating a promising combination therapy approach.
These findings illustrate how cancer cells exploit multiple layers of gene regulation and how understanding these interconnected pathways can yield smarter, more effective treatments.
Qi Cao, PhD, Anthony J. Schaeffer, MD, Professor of Urology and co-senior author, emphasizes that the study opens new questions about EZH2’s roles beyond its canonical functions, particularly in regulating RNA biology in prostate cancer. Co-senior author Rendong Yang, PhD, along with Feinberg colleagues Ertugrul Özbudak, Sarki Abdulkadir, MD, PhD, and Daniel Arango, PhD, contributed to the work. Additional authors hail from Northwestern’s Robert H. Lurie Comprehensive Cancer Center.
Funding supported the project in part through Northwestern startup funds and a suite of grants, including from the U.S. Department of Defense, the National Institutes of Health, the Elsa U. Pardee Foundation, and the Polsky Urologic Cancer Institute.
This research highlights the complex interplay between epigenetic regulation and RNA biology in cancer and points to a potentially powerful strategy: targeting EZH2 in combination with m6A pathway inhibitors to curb tumor growth in prostate cancer. As researchers continue to dissect EZH2’s broader roles, the goal remains clear — translate these insights into more effective therapies for patients.
