UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma.
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.
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.
Raksha
R
Mudbhary
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.
Yujin
Y
Hoshida
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.
Yelena
Y
Chernyavskaya
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.
Vinitha
V
Jacob
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.
Augusto
A
Villanueva
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
M Isabel
MI
Fiel
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.
Xintong
X
Chen
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.
Kensuke
K
Kojima
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Swan
S
Thung
Rodent Histopathology Core Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
Roderick T
RT
Bronson
Liver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Anja
A
Lachenmayer
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.
Kate
K
Revill
HCC Translational Research Laboratory, IDIBAPS, CIBEREHD, Hospital Clinic, University of Barcelona, Catalonia 08036, Spain.
Clara
C
Alsinet
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Ravi
R
Sachidanandam
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Anal
A
Desai
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sucharita
S
SenBanerjee
Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chinweike
C
Ukomadu
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.
Josep M
JM
Llovet
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.
Kirsten C
KC
Sadler
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D015331:Cohort Studies; D019295:Computational Biology; D019175:DNA Methylation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015027:Zebrafish
D022762:CCAAT-Enhancer-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases