The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430030, China; State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
Cancer Cell. 2019 Apr 15;35(4):633-648.e7. doi: 10.1016/j.ccell.2019.03.003. Epub 2019 Apr 4.
UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.
UHRF1 有助于在哺乳动物细胞中建立和维持 DNA 甲基化模式。已经定义了建立域，包括 E3 连接酶功能，但维护域的特征描述较差。在这里，我们证明 UHRF1 的组蛋白和半甲基化 DNA 结合功能，但不是 E3 连接酶活性，可维持人类结直肠癌（CRC）细胞中的癌症特异性 DNA 甲基化。破坏任一染色质阅读器活性都会逆转 DNA 过度甲基化，重新激活表观遗传沉默的肿瘤抑制基因（TSGs），并降低 CRC 的致癌特性。此外，高 UHRF1 与低 TSG 表达之间的反比关系与 CRC 的进展和降低的患者存活率相关。确定关键的 UHRF1 结构域功能及其与 CRC 预后的关系，为开发靶向该蛋白的治疗性 DNA 去甲基化剂提供了方向和价值。
