Northwestern Medicine scientists have uncovered an unexpected role for a well-known cancer-related protein, revealing a new layer of genetic regulation that could reshape how certain cancers are treated.
In a new study published in Nature Communications, investigators found that EZH2 — a protein long recognized for its role in modifying DNA-packaging histones — also plays a direct and previously unknown role in RNA editing in prostate cancer. The discovery links two major epigenetic processes and helps explain why RNA editing patterns are frequently disrupted in tumors, said Yang Yi, PhD, assistant professor of Urology and first author of the study.
“EZH2 is a well-known oncogene in prostate cancer, but our work focuses on uncovering its non‑canonical functions — especially how it interacts with RNA modifications,” Yi said.
RNA editing, specifically a process called adenosine-to-inosine (A-to-I) editing, allows cells to alter RNA messages after they are transcribed from DNA. This mechanism, carried out by enzymes known as ADARs (adenosine deaminases acting on RNA), is common in animals and helps fine-tune gene expression. In cancer, however, RNA editing often goes awry, allowing the tumor to grow and survive. Until now, the molecular drivers of these altered editing patterns have remained poorly understood.
“We observed a direct interaction between EZH2 and ADAR, the enzyme that conducts A‑to‑I RNA editing, and this interaction reshapes the global RNA editing pattern in cancer cells,” Yi said. “Our findings may help explain why targeting EZH2 alone has shown limited success in solid tumors: because EZH2 can indirectly stabilize oncogenic transcripts and increase their expression.”
The new research identifies EZH2 as a key regulator of ADAR1, the main RNA-editing enzyme active in many cancers. EZH2 is widely studied because it is frequently overactive in tumors and is already the target of several experimental and approved cancer drugs. The surprise, investigators said, is that EZH2’s newly discovered function in RNA editing operates independently of its enzymatic activity.
At the molecular level, the team found that EZH2 physically interacts with ADAR1, competing with another protein, interleukin enhancer binding factor 2 (ILF2), for access to the RNA-editing enzyme. By displacing ILF2, EZH2 changes which RNA molecules ADAR1 acts on, resulting in a “bidirectional” effect: boosting the editing of some RNA targets while reducing others. This altered editing landscape helps cancer cells maintain the expression of genes that promote tumor growth.
“We show how EZH2 and ADAR1 work together to control RNA biology, which adds an entirely new layer to how we think about gene regulation in cancer,” said Qi Cao, PhD, the Anthony J. Schaeffer, MD, Professor of Urology, and senior author of the study.
The study’s findings also carry promise for future therapies, Cao said. The investigators showed that removing ADAR1 makes cancer cells and tumors far more sensitive to drugs that selectively degrade EZH2, suggesting that targeting both pathways together could deliver a stronger anti-cancer punch than attacking EZH2 alone.
“Our study suggests that targeting EZH2 through its RNA‑related functions — rather than only its chromatin activity — may lead to better therapeutic outcomes,” Cao said.
Beyond prostate cancer, the investigators believe the EZH2–ADAR1 connection could have broad relevance, as both proteins are implicated in multiple tumor types. Taken together, the findings highlight how cancer cells exploit crosstalk between chromatin regulation and RNA processing to gain growth advantages, and how those same connections may expose new vulnerabilities, Cao said.
Yi and Cao are both members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Additional Feinberg co-authors of the study included Edward Schaeffer, MD, PhD, the chair and Harold Binstein Professor of Urology, and Lu Wang, PhD, assistant professor of Biochemistry and Molecular Genetics.
The study was supported by startup funding provided by Northwestern University, as well as American Cancer Society grant RSG-15-192-01; Prostate SPORE P50CA180995; U.S. Department of Defense grants W81XWH-17-1-0357, W81XWH-19-1-0563 and W81XWH-20-1-0504; National Institutes of Health grants R01CA256741, R01CA285684, R01CA300246 and R01CA278832; and the Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital.
