Dysfunction of DNA repair is a key driver of cancer. Understanding the molecular mechanisms behind dysfunctional DNA repair in cancer cells is crucial for the occurrence of cancer and the development of new therapies. Recently, in a research report titled "EZH2 directly methylates PARP1 and regulates its activity in cancer" published in the international journal Science Advances, scientists from Northwestern University and other institutions discovered a new molecular mechanism behind dysfunctional DNA repair in prostate cancer cells through research. This research finding is expected to guide scientists to develop new targeted therapies to treat prostate cancer patients who are resistant to current standard therapies.
DNA damage is a natural phenomenon that occurs in cells caused by a variety of intracellular and extracellular stress factors. However, if it is not repaired, this damage can lead to gene mutations, which can lead to the occurrence of different diseases, including cancer. In this study, researchers studied a variety of human prostate cancer cell lines and found that the EZH2 protein can directly methylate and regulate the activity of poly (ADP-ribose) polymerase-1 (PARP1). PARP1 is an essential enzyme involved in DNA repair, and EZH2 is a known oncogene in solid tumors that has also been identified as a specific transcriptional repressor.
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The researchers found that EZH2-mediated methylation has a dual role. On the one hand, it can inhibit the repair of DNA damage associated with the catalytic activity of PARP1. On the other hand, it can also protect cells from excessive consumption of nicotinamide adenine dinucleotide, a coenzyme that is very important for cell metabolism, during the formation of DNA damage. In addition, the researchers pointed out that EZH2-mediated methylation can regulate the transcription and oncogenic activity of PARP1 to a certain extent by damaging the interaction between PARP1 and the E2F1 gene (known to be highly expressed in cancer cells) and the activity of the E2F1 transcription factor.
Figure 1. Schematic diagram depicting the role of EZH2 reported by this study. (Meng Q, et al., 2024)
These findings reveal how EZH2 directly regulates PARP1 activity during damaged DNA repair and cancer progression, and build on previous findings by scientists. In addition, the findings suggest that targeting both EZH2 and PARP1 could be a potential therapeutic approach to treat cancer patients who have become resistant to PARP1 inhibitors. "EZH2 and PARP1 inhibitors work together to inhibit prostate cancer growth, so we have to target them both to achieve the best therapeutic effect for patients," said Cao.
PARP1 inhibitors are now FDA-approved for treating many different types of cancer, including breast and prostate cancer. But they are only used for cancer types that have homologous recombination defects, such as cancers with BRCA1 and BRCA2 mutations. Therefore, scientists are currently working hard to find a broader way to use PARP1 inhibitors in different types of cancer, which is why they consider the importance of combining EZH2 and PARP1. In summary, this study reveals the molecular mechanism behind the functional fine-tuning of PARP1 activity by EZH2 during DNA damage repair and cancer progression, which provides a certain theoretical basis for the combined targeting of EZH2 and PARP1 to treat cancer.
Reference
Meng Q, et al. EZH2 directly methylates PARP1 and regulates its activity in cancer. Science Advances, 2024, 10(48): eadl2804.