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

UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma.

Author information

1
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
HCC Translational Research Laboratory, IDIBAPS, CIBEREHD, Hospital Clinic, University of Barcelona, Catalonia 08036, Spain; Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London, London SE5 9RS, UK.
5
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Rodent Histopathology Core Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
7
Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
HCC Translational Research Laboratory, IDIBAPS, CIBEREHD, Hospital Clinic, University of Barcelona, Catalonia 08036, Spain.
10
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
11
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
12
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; HCC Translational Research Laboratory, IDIBAPS, CIBEREHD, Hospital Clinic, University of Barcelona, Catalonia 08036, Spain; Institució Catalana de Recerca i Estudis Avançats Lluís Companys, Barcelona 08010, Spain.
13
Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: kirsten.edepli@mssm.edu.

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.

PMID:
24486181
PMCID:
PMC3951208
DOI:
10.1016/j.ccr.2014.01.003
[Indexed for MEDLINE]
Free PMC Article

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