Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties
Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties
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定义支持维持人类结肠癌 DNA 甲基化和致癌特性的 UHRF1 结构域。
DOI：
10.1016/j.ccell.2019.03.003
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发表时间：
2019-04-15
期刊：
影响因子：
50.3
通讯作者：
Baylin, Stephen B.
中科院分区：
文献类型：
--
作者：
Kong, Xiangqian;Chen, Jie;Baylin, Stephen B.
Uhrf1有助于在哺乳动物细胞中建立和维持DNA甲基化模式。建立结构域已被定义，包括E3连接酶功能，但维持结构域未得到很好的描述。在这里，我们证明了uhrf1组蛋白和半甲基化的DNA结合功能，而不是E3连接酶活性，维持了人类结直肠癌(CRC)细胞中癌症特异性DNA甲基化。破坏任何一个染色质阅读器的活性都会逆转DNA的超甲基化，重新激活表观遗传沉默的肿瘤抑制基因(TSG)，并降低CRC的致癌特性。此外，uhrf1的高表达和TSG的低表达之间的负相关性与CRC的进展和患者存活率的降低密切相关。确定关键的uhrf1结构域功能及其与结直肠癌预后的关系为以该蛋白为靶点开发治疗性DNA去甲基化药物提供了方向和价值。
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.