Targeting SUV4-20H epigenetic enzymes as therapeutic strategy for enhancing topoisomerase II poisoning in prostate cancer

DNA topoisomerase II (TOP2) plays a crucial role in DNA-associated processes by inducing transient DNA double-strand breaks, making it an important target for DNA-damage stabilizing agents. Commonly used in cancer therapy, these agents are designed to interfere with TOP2 cleavage complexes on chromatin. However, the epigenetic pathways influencing their effectiveness and the resultant cellular responses remain elusive. Here, we combine in vitro as well as in vivo genetic and pharmacological approaches in prostate cancer to demonstrate that inhibiting the histone H4-lysine 20 (H4K20) methyltransferases SUV4-20H1 and SUV4-20H2 induces synthetic lethality when combined with TOP2 poisons, such as etoposide. Remarkably, we show that the loss of SUV4-20H enzymes, which prevents the conversion of H4K20 mono-methylation to higher methylation states, has minimal impact on prostate cancer cell behavior under normal conditions. However, these innocuous epigenetic changes significantly enhances the trapping of TOP2 complex in chromatin and increases DNA damage in response to etoposide. Furthermore, SUV4-20H depletion impairs the repair of TOP2-induced DNA breaks by disrupting the switch from RPA to RAD51 foci at damage sites, leading to extensive cancer cell death and inhibition of prostate tumor growth. Overall, these findings suggest that dual targeting of SUV4-20H and TOP2 activity on chromatin represents a promising therapeutic strategy for prostate cancer, where SUV4-20H2 emerges as a potential marker of aggressive disease and high metastatic risk.