title: Mallory-Denk bodies form when EZH2/H3K27me3 fails to methylate DNA in the nuclei of human and mice liver cells.
abstract: EZH2/H3K27me3 and polycomb group complex (PcG) play a major role in regulating global gene expression including tumor suppressor genes. EZH2 is linked to cell cycle regulated EZH2 phosphorylation by CDK1, a mitotic kinase which increases in arrested mitosis compared to S phase. CDK1 phosphorylation of EZH2 accelerates the degradation of pEZH2. Phospho-EZH2 is subjected to ubiquitination. The half-like of pEZH2 is shorter when compared to total EZH2. In the present study, pEZH2 was found concentrated together with ubiquitin in the Mallory-Denk bodies (MDB) that were formed in hepatocytes in the livers of drug primed mice refed DDC and humans with alcoholic hepatitis or hepatocellular carcinoma. The cells that formed MDBs in the mice livers studied were associated with a growth advantage and a high proliferative index. However, the livers from patients with alcoholic hepatitis showed evidence of cell cycle arrest where PCNA, cyclin D1 and p27 positive nuclei were numerous but Ki-67 positive nuclei were scarce. It is concluded that MDB formation is linked to the cell cycle and global gene expression (i.e. loss of gene silencing) through its association with the regulation of the polycomb group PRC2/EZH2/H3K27me3 complex.
authors.affiliation: Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA 90509, USA. sfrench@labiomed.org
authors.forename: B A
authors.initials: BA
authors.lastname: French
authors.forename: J
authors.initials: J
authors.lastname: Oliva
authors.forename: F
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Zhong
authors.forename: V
authors.initials: V
authors.lastname: Buslon
authors.forename: S W
authors.initials: SW
authors.lastname: French
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D006519:Hepatitis, Alcoholic / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D059609:Mallory Bodies / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008745:Methylation; D051379:Mice; D008854:Microscopy, Electron; D063151:Polycomb Repressive Complex 2; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D018809:Proliferating Cell Nuclear Antigen; D011725:Pyridines; D014157:Transcription Factors; C513554:diethyl 1,4-dihydro-1,4,6-trimethyl-3,5-pyridinedicarboxylate; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012436:S-Adenosylmethionine; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine