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.

前列腺癌（Prostate cancer, PC）是全球范围内导致男性死亡率升高的重要因素之一，但其异质性的潜在分子机制仍未阐明。众所周知，表观遗传修饰在癌症进展中发挥关键作用。肿瘤抑制基因启动子区域的异常甲基化，是前列腺癌发生发展过程中最主要的表观遗传改变。泛素样PHD和环指结构域包含蛋白1（Ubiquitin-like PHD and RING finger domain-containing protein 1, UHRF1）在人体内又被称为ICBP90，是维持DNA甲基化所必需的蛋白。UHRF1可通过其SET和RING相关（SET and RING-associated, SRA）结构域识别甲基化CpG序列，并将DNA甲基转移酶1（DNA methyltransferase 1, DNMT1）直接锚定至复制焦点。但目前学界仍不清楚UHRF1如何精准且高效地调控前列腺癌中的基因表达网络。本研究证实，UHRF1可通过其SRA基序及内在无序区2形成相分离液滴。进一步研究发现，UHRF1可在多种肿瘤抑制基因（tumor suppressor genes, TSGs）的启动子区域形成核凝集体，并招募DNMT1以介导表观遗传基因沉默，最终促进前列腺癌细胞的恶性增殖。上述研究结果揭示，UHRF1的相分离在前列腺癌的发病机制中具有至关重要的作用。