title: Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers.
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.
authors.affiliation: Biomedical Sciences Research Center Al. Fleming, Vari, Greece.
authors.forename: Kostas C
authors.initials: KC
authors.lastname: Nikolaou
authors.affiliation: Biomedical Sciences Research Center Al. Fleming, Vari, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Moulos
authors.affiliation: Department of Biology University of Crete, Herakleion, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Chalepakis
authors.affiliation: Biomedical Sciences Research Center Al. Fleming, Vari, Greece.
authors.forename: Pantelis
authors.initials: P
authors.lastname: Hatzis
authors.affiliation: Medical Institute of Bioregulation Kyusyu University, Fukuoka, Japan Gastrointestinal and Oncology Division, National Kyusyu Cancer Center, Fukuoka, Japan.
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Oda
authors.affiliation: HHMI, Department of Biochemistry, New York University School of Medicine, New York, NY USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
authors.affiliation: Biomedical Sciences Research Center Al. Fleming, Vari, Greece talianidis@fleming.gr.
authors.forename: Iannis
authors.initials: I
authors.lastname: Talianidis
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D014407:Tumor Cells, Cultured
chemical_list: D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; C529566:KMT5a protein, mouse
keywords: ductal progenitors; hepatocellular carcinoma; histone methylase