| Literature DB >> 24486181 |
Raksha Mudbhary1, Yujin Hoshida2, Yelena Chernyavskaya3, Vinitha Jacob1, Augusto Villanueva4, M Isabel Fiel5, Xintong Chen2, Kensuke Kojima2, Swan Thung5, Roderick T Bronson6, Anja Lachenmayer7, Kate Revill8, Clara Alsinet9, Ravi Sachidanandam10, Anal Desai11, Sucharita SenBanerjee11, Chinweike Ukomadu11, Josep M Llovet12, Kirsten C Sadler13.
Abstract
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.Entities:
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Year: 2014 PMID： 24486181 PMCID： PMC3951208 DOI： 10.1016/j.ccr.2014.01.003
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743