title: Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis.
abstract: There is clinical evidence that chronic liver diseases in which MDBs (Mallory Denk Bodies) form progress to hepatocellular carcinoma. The present study provides evidence that links MDB formation induced by chronic drug injury, with preneoplasia and later to the formation of tumors, which develop long after drug withdrawal. Evidence indicated that this link was due to an epigenetic cellular memory induced by chronic drug ingestion. Microarray analysis showed that the expressions of many markers of preneoplasia (UBD, Alpha Fetoprotein, KLF6 and glutathione-S-transferase mu2) were increased together when the drug DDC was refed. These changes were suppressed by S-adenosylmethionine feeding, indicating that the drug was affecting DNA and histones methylation in an epigenetic manner. The link between MDB formation and neoplasia formation was likely due to the over expression of UBD (also called FAT10), which is up regulated in 90% of human hepatocellular carcinomas. Immunohistochemical staining of drug-primed mouse livers showed that FAT10 positive liver cells persisted up to 4 months after drug withdrawal and they were still found in the livers of mice, 14 months after drug withdrawal. The refeeding of DDC increased the percent of FAT10 hepatocytes.
authors.affiliation: Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson Street Torrance, CA 90509, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Oliva
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: Barbara A
authors.initials: BA
authors.lastname: French
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Laron
authors.initials: L
authors.lastname: McPhaul
authors.forename: Fataneh
authors.initials: F
authors.lastname: Amidi
authors.forename: Jeniffer
authors.initials: J
authors.lastname: Dedes
authors.forename: Amir
authors.initials: A
authors.lastname: Habibi
authors.forename: Sheila
authors.initials: S
authors.lastname: Nguyen
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000633:toxicity; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D004095:Dihydropyridines; C512253:FAT10 protein, mouse; D006877:Hydroxamic Acids; C488922:Mallory body protein, mouse; D011506:Proteins; D014452:Ubiquitins; C061879:diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate; C066024:PCA 4248; C012589:trichostatin A