UHRF1 phase separation mediates stable inheritance of DNA methylation and promotes the proliferation of prostate cancer cells

The primary epigenetic alteration in the development of prostate cancer (PC) is aberrant methylation of the promoter region of tumor suppressor genes. Maintaining DNA methylation activity requires ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1). Through its SET and RING-associated (SRA) domain, UHRF1 identifies methylated cytosine-phosphate-guanine sequences and binds DNA methyltransferase 1 (DNMT1) directly to replicated DNA foci. Nevertheless, the modality used by UHRF1 to regulate gene networks in PC cells precisely and efficiently is unknown. Research has indicated that epigenetic modification is significantly influenced by the phase separation of epigenetic regulators. Thus, the purpose of this work was to find out if UHRF1 phase separation is a mechanism for PC cells to inherit DNA methylation in a stable manner. We evaluated the correlation between UHRF1 expression level and PC development, as well as used PC cell lines to study the mechanism of UHRF1 phase separation driving the progression of PC. The results of this study demonstrated that UHRF1 formed phase-separated droplets by its SRA motif and intrinsically disordered region 3. Furthermore, UHRF1 formed nuclear condensates at the promoter region of multiple cancer-related genes and recruited DNMT1 to allow epigenetic gene silencing that led to malignant proliferation of PC cells. These results revealed that phase separation of UHRF1 is crucial for PC pathogenesis.