UHRF1 Is an Oncogene that Promotes DNA Hypomethylation

Global DNA hypomethylation is a hallmark of human cancer cells. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) maintains methylation patterns following DNA replication through recruitment of DNA methyltransferase 1 (DMNT1) and has previously been implicated in liver outgrowth in zebrafish. To determine whether UHRF1 overexpression is sufficient to alter global methylation patterns and promote hepatocellular carcinoma (HCC), Mudbhary and colleagues generated transgenic zebrafish that expressed varying levels of a human UHRF1–GFP fusion in a hepatocyte-specific manner. Reduced liver size and increased mortality were detected in larvae expressing high levels of UHRF1–GFP (UHRF1-GFP High) starting 5 days after fertilization in association with significant DNA hypomethylation and DNMT1 mislocalization and destabilization. In addition, UHRF1-GFP High livers showed elevated senescence-associated β-galactosidase staining, reduced cell proliferation, and increased expression of p53 and its downstream target genes. Hypomethylation and p53-induced senescence were the primary mechanisms of disrupted hepatic outgrowth, as the microliver phenotype in UHRF1-GFP High larvae could be partially reversed by ectopic DNMT1 expression or deletion of one copy of Tp53. However, in later larval stages, UHRF1-GFP High livers showed reduced senescence and increased proliferation, which were associated with an increased incidence of dysplastic foci and HCC. In these larvae, p53 suppressed tumor formation downstream of UHRF1, as the removal of one copy of Tp53 significantly increased the incidence of HCC incidence. Importantly, UHRF1 is overexpressed in human HCC and other tumor types, and high UHRF1 expression is associated with early recurrence and decreased survival as well as with TP53 inactivating mutations and downregulation of a p53-induced senescence gene signature in HCC. Together, these results implicate UHRF1 as an oncogene and suggest that global DNA hypomethylation induced by UHRF1 overexpression induces a p53-mediated senescence program that is bypassed in HCC.

Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 2014;25:196–209.