UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma

Cancer Cell. 2014 Feb 10;25(2):196-209. doi: 10.1016/j.ccr.2014.01.003. Epub 2014 Jan 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology*
  • Cells, Cultured
  • Cellular Senescence
  • Cohort Studies
  • Computational Biology
  • DNA Methylation*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Immunoblotting
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Mutation / genetics
  • Prognosis
  • Survival Rate
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Zebrafish

Substances

  • CCAAT-Enhancer-Binding Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • UHRF1 protein, human

Associated data

  • GEO/GSE52605