Targeting Novel Molecular Mechanisms May Repair Damaged DNA

Northwestern Medicine investigators have discovered new molecular mechanisms underlying DNA repair dysregulation in prostate cancer cells, findings that may inform the development of new targeted therapies for patients that have become resistant to standard treatments, according to a recent study published in Science Advances.  

Qi Cao, PhD, the Anthony J. Schaeffer, MD, Professor of Urology, was senior author of the study.  

DNA damage is a natural occurrence in cells caused by various intercellular and external stressors. However, if left unrepaired, this damage can lead to genetic mutations that can lead to the development of different diseases, including cancer.  

In the current study, Cao’s team studied multiple human prostate cancer cell lines and discovered that the EZH2 protein directly methylates and regulates the activity of poly (ADP–ribose) polymerase-1 (PARP1), an essential enzyme involved in DNA repair. EZH2 is a well-known oncogene found in solid tumors and has also been identified as a transcription repressor. 

The role of this EZH2- mediated methylation is two-fold, the scientists discovered. On one hand, it represses PARP1 catalytic activity and associated DNA damage repair. On the other hand, it also protects cells from overconsuming nicotinamide adenine dinucleotide – a coenzyme that is essential for cellular metabolism – during DNA damage formation.  

Furthermore, the investigators found that EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity in part by impairing an interaction between PARP1 and the E2F1 gene, which is known to be highly expressed in cancer cells, and the activity of E2F1 transcription factors.  

The findings demonstrate how EZH2 directly modulates PARP1 activity during the repair of damaged DNA and cancer progression, building on findings in previous work from Cao’s laboratory.   

The study also suggests that targeting both EZH2 and PARP1 simultaneously may be a promising therapeutic approach for patients with cancer who have developed resistance to PARP1 inhibitors, according to the authors.  

“EZH2 and PARP1 inhibitors synergistically suppress prostate cancer growth,” Cao said. “So we have to target them at the same time to achieve the best therapeutic efficacy.” 

“PARP1 inhibitors have been approved by FDA in different cancer types, including breast cancer and prostate cancer, but they’re only used in homologous recombination deficient cancer types – for example, the BRCA1 and BRCA2 mutations. So, people are trying to find more broader ways to use PARP1 inhibitors in different types of cancers, and that is why we consider the importance of the EZH2 and PARP1 combination,” said Qingshu Meng, PhD, a postdoctoral fellow in the Cao laboratory and co-first author of the study. 

Co-authors of the study included Yang Yi, PhD, assistant professor of Urology, and Rendong Yang, PhD, associate professor of Urology.  

Cao, Yi and Yang are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.  

This work was supported by a start-up fund provided by Northwestern University; the Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University; U.S. Department of Defense grants W81XW-20-1-0504 and W81XW-17-1-0357; National Institutes of Health/National Cancer Institute grants R01A208257, R01A256741, R01A285684, and Prostate SPORE P50A180995 Development Research Program; National Institutes of Health grant GM152207; American Cancer Society Research Scholar Award RSG-21-013-01-M; National Institutes of Health grant R01A259388, R35GM142441, and Prostate SPOR P50A180995; National Institutes of Health grants R01GM138407 and R01GM125632; and U.S. Department of Defense grants W81XW-21-1-0146 and 9425-23-1-0491.