Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cancer Cell. 2014 Feb 10;25(2):196-209. doi: 10.1016/j.ccr.2014.01.003. Epub 2014 Jan 30.
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption.
泛素样含 PH 和 RING 指结构域蛋白 1（UHRF1）是一种高度表达于多种癌症中的 DNA 甲基化的必需调控因子。在这里，我们使用转基因斑马鱼、培养细胞和人类肿瘤来证明 UHRF1 是一种癌基因。UHRF1 在斑马鱼肝细胞中的过表达会导致 Dnmt1 的不稳定性和定位改变，从而导致 DNA 低甲基化和 Tp53 介导的衰老。当衰老被绕过时，肝细胞癌（HCC）就会出现。tp53 突变既减轻了衰老，又加速了肿瘤的发生。人类 HCC 重现了这一模式，因为 UHRF1 的过表达定义了具有基因组不稳定性、TP53 突变和破坏 TP53 介导的衰老程序的侵袭性 HCC 的一个亚类。我们提出，UHRF1 的过表达是癌细胞中 DNA 低甲基化的一种机制，而衰老则是由于表观遗传破坏而限制肿瘤发生的主要手段。
