UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma

Raksha Mudbhary, Yujin Hoshida, Yelena Chernyavskaya, Vinitha Jacob, Augusto Villanueva, M. Isabel Fiel, Xintong Chen, Kensuke Kojima, Swan Thung, Roderick T. Bronson, Anja Lachenmayer, Kate Revill, Clara Alsinet, Ravi Sachidanandam, Anal Desai, Sucharita SenBanerjee, Chinweike Ukomadu, Josep M. Llovet, Kirsten C. Sadler

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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.

Original languageEnglish (US)
Pages (from-to)196-209
Number of pages14
JournalCancer Cell
Volume25
Issue number2
DOIs
StatePublished - Feb 10 2014

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Mudbhary, R., Hoshida, Y., Chernyavskaya, Y., Jacob, V., Villanueva, A., Fiel, M. I., Chen, X., Kojima, K., Thung, S., Bronson, R. T., Lachenmayer, A., Revill, K., Alsinet, C., Sachidanandam, R., Desai, A., SenBanerjee, S., Ukomadu, C., Llovet, J. M., & Sadler, K. C. (2014). UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma. Cancer Cell, 25(2), 196-209. https://doi.org/10.1016/j.ccr.2014.01.003