ArticleCancer cell2014
UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma.
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Article in Cancer cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 211 papers.
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211 citing papers in PubMed, 321 citations in OpenAlex.
- UHRF1 overexpression generates distinct senescent states with different Tp53 dependencies.EMBO reports · 2026Article
- Mapping genetic modifiers of epimutation rates identifies VIM2/4 as dosage-sensitive negative regulators of CG methylation maintenance.Nature plants · 2026Article
- DNA Methylation Dynamics in Development and Disease: Insights from Zebrafish Models.Biomedicines · 2026Review
- Article
- ZCCHC4 Orchestrates Hepatocellular Carcinoma Metastasis by Regulating Lipid biosynthesis and TMEM97/LCN2/Twist1 Pathway.International journal of biological sciences · 2026Article
- Arginine methylation in cancer: mechanisms and therapeutic implications.Biomarker research · 2025Review
- Discovery and Characterization of Uracil Derivatives Targeting the Set-and-Ring Domain of UHRF1.Journal of chemical information and modeling · 2025Article
- DNA methylation protects cancer cells against senescence.Nature communications · 2025Article
- UHRF1 phase separation mediates stable inheritance of DNA methylation and promotes the proliferation of prostate cancer cells.Cell communication and signaling : CCS · 2025Article
- Inhibition of epigenetic regulator UHRF1 attenuates renal fibrosis and retains transcription factor Krüppel-like factor 15 expression.Cell death discovery · 2025Article
- DNA Methylation, Aging, and Cancer.Epigenomes · 2025Review
- Exosome-mediated Transfer of lncRNA in Liver Associated Diseases; Uncovered Truths.Cell biochemistry and biophysics · 2025Review
- Systematic analysis of the aberrances and functional implications of epigenetic genes in hepatocellular carcinoma.Discover oncology · 2025Article
- Negative Cooperativity in the UHRF1 TTD-PHD Dual Domain Masks the Contributions of Cation-π Interactions between Trimethyllysine and the TTD Aromatic Cage.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Epigenetic ALYREF/UHRF1/RHOB Axis in Corneal Wound Healing and Implications for Epithelial Tumorigenesis.Investigative ophthalmology & visual science · 2025Article
- Identification of prognosis-related key genes in hepatocellular carcinoma based on bioinformatics analysis.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Article
- Epigenetic Disordering Drives Stemness, Senescence Escape and Tumor Heterogeneity.bioRxiv : the preprint server for biology · 2024Article
- Optimized methods to image hepatic lipid droplets in zebrafish larvae.Disease models & mechanisms · 2024Article
- Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response.Nature communications · 2024Article
- Small-molecule-based targeted therapy in liver cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Review
151 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 6 institutions in 3 countries.
Raksha MudbharyDivision 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.
Yujin HoshidaDivision 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.
Yelena ChernyavskayaDivision 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.
Vinitha JacobDivision 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.
Augusto VillanuevaHCC 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.
M Isabel FielDepartment of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Xintong ChenDivision 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 KojimaDivision 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.
Swan ThungDepartment of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Roderick T BronsonRodent Histopathology Core Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA.
Anja LachenmayerLiver Cancer Program/Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Kate RevillDepartment 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.
Clara AlsinetHCC Translational Research Laboratory, IDIBAPS, CIBEREHD, Hospital Clinic, University of Barcelona, Catalonia 08036, Spain.
Ravi SachidanandamDepartment of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Anal DesaiDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sucharita SenBanerjeeDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chinweike UkomaduDivision of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Josep M LlovetDivision 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.
Kirsten C SadlerDivision 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.
Icahn School of Medicine at Mount Sinai · USHarvard University · USBrigham and Women's Hospital · USConsorci Institut D'Investigacions Biomediques August Pi I Sunyer · ESKing's College London · GBUniversitat de Barcelona · ES
Funding
VectorP30CA006516 · NCI · DANA-FARBER CANCER INSTITUTE · PI A. Heather Eliassen · 1985 to 2026
$330.6MTRAINING PROGRAM IN CANCER THERAPYT32CA078207 · NCI · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI James J Manfredi · 1999 to 2026
$11.6MRole of Uhrf1 in Liver Development, Regeneration and CarciogenesisR01DK080789 · NIDDK · NEW YORK UNIVERSITY · PI Kirsten C Sadler Edepli · 2009 to 2026
$5.2MMolecular Prognostic Indicators in Liver Cirrhosis and CancerR01DK099558 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI HOSHIDA, YUJIN · 2013 to 2016
$2.6MIntegrative genomic analysis in hepatocellular carcinomaR01DK076986 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI LLOVET, JOSEP M · 2007 to 2011
$1.3MRapid and inexpensive epi/genetic profiling of the human mitochondrial genomeR21HG007394 · NHGRI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI SACHIDANANDAM, RAVI · 2013 to 2014
$465kThe Cell-autonomous Contributions of UHRF1 to Liver Development and RegenerationF30DK094503 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI JACOB, VINITHA · 2011 to 2014
$181kNCI NIH HHS 5P30CA006516-45NCI NIH HHS P30 CA006516NCI NIH HHS T32 CA078207NCI NIH HHS T32CA078207-14NHGRI NIH HHS R21 HG007394NIDDK NIH HHS 1R01DK076986NIDDK NIH HHS 1R01DK099558NIDDK NIH HHS 5R01DK080789-02NIDDK NIH HHS F30 DK094503NIDDK NIH HHS F30DK094503NIDDK NIH HHS R01 DK076986NIDDK NIH HHS R01 DK080789NIDDK NIH HHS R01 DK099558
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.
Indexed as
DNA MethylationAnimalsCarcinoma, HepatocellularCCAAT-Enhancer-Binding ProteinsCells, CulturedCellular SenescenceCohort StudiesComputational BiologyHepatocytesHumansImmunoblottingLiverLiver NeoplasmsMutationPrognosisSurvival RateCCAAT-Enhancer-Binding ProteinsTP53 protein, humanTumor Suppressor Protein p53Ubiquitin-Protein LigasesUHRF1 protein, human
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