Biology subjects

JULIEN, E.

Publications and source records attributed to JULIEN, E..

3 recordsLinked to original sources

bioRxiv2025

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.

cancer biology↗

bioRxiv2023

Cell-cycle dependent inhibition of BRCA1 signaling by the lysine methyltransferase SET8

The cell-cycle regulated methyltransferase SET8 is the sole enzyme responsible for the mono-methylation of histone H4 at lysine 20 (H4K20) that is the substrate for di- and tri-methylation mainly by SUV4-20Hs enzymes. Both SET8 and SUV4-20Hs have been implicated in regulating DNA repair pathway choice through the inverse affinities of BRCA1-BARD1 and 53BP1 complexes for disparate methylation states of H4K20. However, the precise and respective functions of each H4K20 methyltransferases in DNA repair pathways remained to be clarified. Here, we show that SET8 acts as a potent chromatin inhibitor of homologous recombination and that its timely degradation during DNA replication is essential for the spontaneous nuclear focal accumulation of BRCA1 and RAD51 complexes during S-phase. Strikingly, the anti-recombinogenic function of SET8 is independent of SUV4-20H activity but requires the subsequent recruitment of the ubiquitin ligase RNF168. Moreover, we show that SET8-induced BRCA1 inhibition is not necessarily related to the loss of BARD1 binding to unmethylated histone H4K20. Instead, it is largely caused by the accumulation of 53BP1 in a manner depending on the concerted activities of SET8 and RNF168 on chromatin. Conversely, the lack of SET8 and H4K20 mono-methylation on newly assembly chromatin after DNA replication led to the untimely accumulation of BRCA1 on chromatin at the subsequent G1 phase. Altogether, these results establish the de novo activity of SET8 on chromatin as a primordial epigenetic lock of BRCA1-mediated HR pathway during the cell cycle.

molecular biology↗

bioRxiv2019

Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable. The search for new therapeutic targets is therefore essential. Here we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for histone H4K20 mono-methylation, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Remarkably, primary malignant plasma cells are particularly addicted to SETD8 activity. Indeed, pharmacological inhibition of this enzyme by the chemical compound UNC0379 demonstrated a significantly higher toxicity in MM cells compared to normal cells from the bone marrow microenvironment. Moreover, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and an activation of the p53 canonical pathway, which together leads to an impairment of myeloma cell proliferation and survival. However, UNC0379 treatment triggers a deadly level of replicative stress in p53 deficient MM cells, indicating that the cytotoxicity associated with SETD8 inhibition is independent of the p53 status. Consistent with this, the combination of UNC0379 with the conventional cytotoxic agent melphalan strongly enhances DNA damage and overcomes drug resistance in myeloma cells. Thus, targeting SETD8 could be of therapeutic interest to improve MM treatment in high-risk patients independently of the p53 status.

cancer biology↗