UHRF1 phase separation regulates the expression of tumor suppressor genes to promote the proliferation of prostate cancer cells

Prostate cancer (PC) significantly contributes to increased mortality rates in men globally; however, the underlying mechanism of the heterogeneity in prostate cancer is still unclear. It is well known that epigenetic modifications play a significant role in the progress of cancer. Aberrant methylation of the promoter regions of tumor suppressor genes is the major epigenetic change in PC development. Ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1), also known as ICBP90 in humans, which is required for DNA methylation maintenance. UHRF1 recognizes methylated CpG sequences through its SET and RING-associated (SRA) domain, and directly tethers DNA methyltransferase 1 (DNMT1) to replicated foci. But exactly how UHRF1 orchestrates the gene network in PC precisely and efficiently is unknown. In this study, we demonstrate that UHRF1 forms phase-separated droplets by its SRA motif and intrinsically disordered region 2. Furthermore, UHRF1 forms nuclear condensates at the promoter region of multiple tumor suppressor genes (TSGs) and recruits DNMT1 to execute epigenetic gene silencing that leads to malignant proliferation of PC cells. These results reveal that phase separation of UHRF1 is crucial for PC pathogenesis.