# A novel role for EZH2 in PARP regulation and PARPi-resistance in prostate cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $582,198

## Abstract

Prostate cancer is the leading cause of cancer-related deaths in American men. It is estimated that each
year more than 180,000 new prostate cancer patients will be diagnosed, and approximately 26,000 patients in
the United States will die, primarily due to metastasis. This occurs despite advances in early detection and
treatment. The available treatment options are limited, not very effective, and associated with severe side effects.
Furthermore, prostate cancer patients can develop resistance to the currently available therapeutics. Therefore,
this proposal will help develop effective treatments and address mechanisms of therapeutic resistance for men
with metastatic prostate cancer.
 Enhancer of zest homolog 2 (EZH2) specifically modifies the histone H3 protein at its lysine 27; thereby,
tightly winding DNA and silencing gene expression. Our previous work showed that EZH2 is upregulated in
advanced prostate carcinomas and metastatic prostate cancer, and prostate cancer patients who have higher
expression levels of EZH2 have shorter survival times than prostate cancer patients with low or no expression
of EZH2. We also found that high expression levels of EZH2 induce chromosome instability by repressing many
important proteins that are responsible for repair of DNA damage. DNA damage and improper DNA repair can
lead to the initiation and progression of many cancers, including prostate cancer. Recently, pharmacological
inhibitors of Poly ADP-ribose polymerases (PARPs) have been clinically tested for the treatment of prostate
cancer; however, these drugs are only effective in a subset of patients with DNA repair defects. Furthermore,
patients can develop therapeutic resistance to PARP inhibitors. Therefore, treatment with PARP inhibitors alone
may not be effective for every patient, suggesting the importance of other biological mechanisms in regulating
the development and progression of prostate cancer.
 Most advanced prostate cancer cells have higher levels of EZH2 and PARP1 proteins compared to that in
early-stage prostate cancer cells, suggesting the importance of these proteins in prostate cancer progression.
We found that EZH2 directly interacts with and methylates a lysine of PARP1. In the proposed project, we will
identify precisely how EZH2-mediated PARP1 lysine methylation regulates PARP1’s function in DNA damage
repair and transcription activity. Understanding these mechanisms will lead to the future design of new inhibitors
of EZH2 and PARP1. Furthermore, our preliminary data strongly suggest that PARPi-resistant tumors have
higher levels of EZH2 compared to PARPi-sensitive tumors, suggesting EZH2 plays a critical role in PARPi-
resistance. Therefore, our work provides a novel rationale to target EZH2 in PARPi-resistant PCa.

## Key facts

- **NIH application ID:** 10979397
- **Project number:** 1R01CA285684-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Qi Cao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,198
- **Award type:** 1
- **Project period:** 2024-07-12 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979397

## Citation

> US National Institutes of Health, RePORTER application 10979397, A novel role for EZH2 in PARP regulation and PARPi-resistance in prostate cancer (1R01CA285684-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10979397. Licensed CC0.

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