Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Cancer Cell. 2019 Apr 15;35(4):633-648.e7. doi: 10.1016/j.ccell.2019.03.003. Epub 2019 Apr 4.


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.

Keywords: UHRF1; colorectal cancer prognosis; domain functions; maintenance DNA methylation; next-generation DNA demethylating agents; oncogenic properties; tumor suppressor gene silencing.

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*
  • Caco-2 Cells
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • CpG Islands
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Mutation
  • Neoplasm Metastasis
  • PHD Zinc Fingers
  • Prognosis
  • Time Factors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • CCAAT-Enhancer-Binding Proteins
  • Histones
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases