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 Sadler Edepli

    Research output: Contribution to journalArticle

    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

    Fingerprint

    Hepatocellular Carcinoma
    DNA
    Zebrafish
    RING Finger Domains
    Cultured Tumor Cells
    Neoplasms
    Mutation
    Genomic Instability
    Cell Aging
    DNA Methylation
    Ubiquitin
    Oncogenes
    Epigenomics
    Hepatocytes
    Carcinogenesis

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

    Cite this

    Mudbhary, R., Hoshida, Y., Chernyavskaya, Y., Jacob, V., Villanueva, A., Fiel, M. I., ... Sadler Edepli, K. (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

    UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma. / Mudbhary, Raksha; Hoshida, Yujin; Chernyavskaya, Yelena; Jacob, Vinitha; Villanueva, Augusto; Fiel, M. Isabel; Chen, Xintong; Kojima, Kensuke; Thung, Swan; Bronson, Roderick T.; Lachenmayer, Anja; Revill, Kate; Alsinet, Clara; Sachidanandam, Ravi; Desai, Anal; SenBanerjee, Sucharita; Ukomadu, Chinweike; Llovet, Josep M.; Sadler Edepli, Kirsten.

    In: Cancer Cell, Vol. 25, No. 2, 10.02.2014, p. 196-209.

    Research output: Contribution to journalArticle

    Mudbhary, R, Hoshida, Y, Chernyavskaya, Y, Jacob, V, Villanueva, A, Fiel, MI, Chen, X, Kojima, K, Thung, S, Bronson, RT, Lachenmayer, A, Revill, K, Alsinet, C, Sachidanandam, R, Desai, A, SenBanerjee, S, Ukomadu, C, Llovet, JM & Sadler Edepli, K 2014, 'UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma', Cancer Cell, vol. 25, no. 2, pp. 196-209. https://doi.org/10.1016/j.ccr.2014.01.003
    Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI et al. UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma. Cancer Cell. 2014 Feb 10;25(2):196-209. https://doi.org/10.1016/j.ccr.2014.01.003
    Mudbhary, Raksha ; Hoshida, Yujin ; Chernyavskaya, Yelena ; Jacob, Vinitha ; Villanueva, Augusto ; Fiel, M. Isabel ; Chen, Xintong ; Kojima, Kensuke ; Thung, Swan ; Bronson, Roderick T. ; Lachenmayer, Anja ; Revill, Kate ; Alsinet, Clara ; Sachidanandam, Ravi ; Desai, Anal ; SenBanerjee, Sucharita ; Ukomadu, Chinweike ; Llovet, Josep M. ; Sadler Edepli, Kirsten. / UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma. In: Cancer Cell. 2014 ; Vol. 25, No. 2. pp. 196-209.
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