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

• Published in: The EMBO journal Vol. 34; no. 4; pp. 430 - 447
• Main Authors: Nikolaou, Kostas C, Moulos, Panagiotis, Chalepakis, George, Hatzis, Pantelis, Oda, Hisanobu, Reinberg, Danny, Talianidis, Iannis
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 12.02.2015; Nature Publishing Group UK; BlackWell Publishing Ltd
• Subjects: Animals; Apoptosis; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - metabolism; Deoxyribonucleic acid; DNA; DNA damage; ductal progenitors; EMBO03; EMBO09; EMBO11; Gangrene; hepatocellular carcinoma; histone methylase; Histone-Lysine N-Methyltransferase - metabolism; Histones - metabolism; Inactivation; Liver cancer; Liver Neoplasms - enzymology; Liver Neoplasms - metabolism; Male; Methylation; Mice; Neoplastic Stem Cells - enzymology; Rodents; Stem cells; Tumor Cells, Cultured; Tumors; histone methylase; hepatocellular carcinoma; ductal progenitors
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201489279

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. Synopsis Loss of the histone H4 lysine 20 mono‐methyltransferase PR‐SET7 in adult mouse hepatocytes causes DNA damage and necrotic cell death followed by tissue inflammation, fibrosis and ROS accumulation. Subsequent aberrant compensatory proliferation of resident progenitor cells with ductal markers elicits the development of hepatocellular carcinoma, providing insights into the controversial origin of hepatic cancer stem cells. Proliferating PR‐SET7‐deficient adult mouse hepatocytes die via necrosis. PR‐SET7‐deficient livers develop hepatocellular carcinoma. The tumors are composed of cells with cancer stem cell (CSC) features. Hepatic CSCs express ductal progenitor markers and re‐express hepatic oncofetal genes (factors that are usually expressed during fetal liver development). Graphical Abstract DNA damage, necrosis and inflammation caused by loss of the histone methyltransferase PR‐SET7 in adult mouse hepatocytes triggers compensatory activation of resident ductal progenitor cells, culminating in hepatocellular carcinoma.