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

doi:10.1016/j.ccr.2014.01.003

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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248 Scopus citations

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 language	English (US)
Pages (from-to)	196-209
Number of pages	14
Journal	Cancer Cell
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2014.01.003
State	Published - Feb 10 2014
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2014.01.003

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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

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, KC 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

@article{f995bb97c47342bda3a78b8182edb180,

title = "UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma",

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.",

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

note = "Funding Information: Financial support was provided by The Breast Cancer Alliance and the March of Dimes (to K.C.S.), a Pilot Project from the DFCI NCI Cancer Center (5P30CA006516-45) and The Sidney A. Swensrud Foundation (to C.U.), the NIH (5R01DK080789-02 to C.U. and K.C.S., 1R01DK099558 to Y.H., 1R01DK076986 to J.M.L., F30DK094503 to V.J., and T32CA078207-14 to Y.C.), the European Commission Seventh Framework Programme FP7-Health 2010 (Heptromic number 259744 to Y.H. and J.M.L.), The Samuel Waxman Cancer Research Foundation, The Spanish National Health Institute (SAF-2010-16055), and the Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (to J.M.L.). Liz Loughlin, Brandon Kent, Meghan Walsh, Alex Mir, Laia Cabellos, Helena Cornell{\`a} Vives, and Sara Toffanin provided expert technical assistance. We are grateful to Sam Sidi for tp53 −/− fish, stimulating discussions, and critical reading of the manuscript. ",

year = "2014",

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day = "10",

doi = "10.1016/j.ccr.2014.01.003",

language = "English (US)",

volume = "25",

pages = "196--209",

journal = "Cancer Cell",

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T1 - UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma

AU - Mudbhary, Raksha

AU - Hoshida, Yujin

AU - Chernyavskaya, Yelena

AU - Jacob, Vinitha

AU - Villanueva, Augusto

AU - Fiel, M. Isabel

AU - Chen, Xintong

AU - Kojima, Kensuke

AU - Thung, Swan

AU - Bronson, Roderick T.

AU - Lachenmayer, Anja

AU - Revill, Kate

AU - Alsinet, Clara

AU - Sachidanandam, Ravi

AU - Desai, Anal

AU - SenBanerjee, Sucharita

AU - Ukomadu, Chinweike

AU - Llovet, Josep M.

AU - Sadler, Kirsten C.

N1 - Funding Information: Financial support was provided by The Breast Cancer Alliance and the March of Dimes (to K.C.S.), a Pilot Project from the DFCI NCI Cancer Center (5P30CA006516-45) and The Sidney A. Swensrud Foundation (to C.U.), the NIH (5R01DK080789-02 to C.U. and K.C.S., 1R01DK099558 to Y.H., 1R01DK076986 to J.M.L., F30DK094503 to V.J., and T32CA078207-14 to Y.C.), the European Commission Seventh Framework Programme FP7-Health 2010 (Heptromic number 259744 to Y.H. and J.M.L.), The Samuel Waxman Cancer Research Foundation, The Spanish National Health Institute (SAF-2010-16055), and the Asociación Española Contra el Cáncer (to J.M.L.). Liz Loughlin, Brandon Kent, Meghan Walsh, Alex Mir, Laia Cabellos, Helena Cornellà Vives, and Sara Toffanin provided expert technical assistance. We are grateful to Sam Sidi for tp53 −/− fish, stimulating discussions, and critical reading of the manuscript.

PY - 2014/2/10

Y1 - 2014/2/10

N2 - 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.

AB - 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.

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DO - 10.1016/j.ccr.2014.01.003

M3 - Article

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SN - 1535-6108

VL - 25

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EP - 209

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

UHRF1 Overexpression Drives DNA Hypomethylation and Hepatocellular Carcinoma

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