EMBO Journal 2015-02-12

Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers.

Kostas C Nikolaou, Panagiotis Moulos, George Chalepakis, Pantelis Hatzis, Hisanobu Oda, Danny Reinberg, Iannis Talianidis

Index: EMBO J. 34(4) , 430-47, (2015)

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Abstract

PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic regenerative cycles coupled with oncogenic STAT3 activation led to the spontaneous development of hepatic tumors composed of cells with cancer stem cell characteristics. These include a capacity to self-renew in culture or in xenografts and the ability to differentiate to phenotypically distinct hepatic cells. Hepatocellular carcinoma in PR-SET7-deficient mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license.