title: A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A.
abstract: The progression of fibrosis in chronic liver disease is dependent upon hepatic stellate cells (HSCs) transdifferentiating to a myofibroblast-like phenotype. This pivotal process is controlled by enzymes that regulate histone methylation and chromatin structure, which may be targets for developing anti-fibrotics. There is limited pre-clinical experimental support for the potential to therapeutically manipulate epigenetic regulators in fibrosis. In order to learn if epigenetic treatment can halt the progression of pre-established liver fibrosis, we treated mice with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep) in a naked form or by selectively targeting HSC-derived myofibroblasts via an antibody-liposome-DZNep targeting vehicle. We discovered that DZNep treatment inhibited multiple histone methylation modifications, indicative of a broader specificity than previously reported. This broad epigenetic repression was associated with the suppression of fibrosis progression as assessed both histologically and biochemically. The anti-fibrotic effect of DZNep was reproduced when the drug was selectively targeted to HSC-derived myofibroblasts. Therefore, the in vivo modulation of HSC histone methylation is sufficient to halt progression of fibrosis in the context of continuous liver damage. This discovery and our novel HSC-targeting vehicle, which avoids the unwanted effects of epigenetic drugs on parenchymal liver cells, represents an important proof-of-concept for epigenetic treatment of liver fibrosis.
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; School of Medicine, Koc University, 34450 Istanbul, Turkey.
authors.forename: Müjdat
authors.initials: M
authors.lastname: Zeybel
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Saimir
authors.initials: S
authors.lastname: Luli
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Sabater
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hardy
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Oakley
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Leslie
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Agata
authors.initials: A
authors.lastname: Page
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Moran Salvador
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sharkey
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, CA 90033, USA.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: The University of Georgia College of Pharmacy, Athens, GA 30602, USA.
authors.forename: David C K
authors.initials: DCK
authors.lastname: Chu
authors.affiliation: The University of Georgia College of Pharmacy, Athens, GA 30602, USA.
authors.forename: Uma Sharan
authors.initials: US
authors.lastname: Singh
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini, 16148 Genova, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini, 16148 Genova, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Perri
authors.affiliation: Experimental Therapy Unit, Laboratory of Oncology, Istituto Giannina Gaslini, 16148 Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Di Paolo
authors.affiliation: Department of Molecular Biology and Genomics, Institute for Molecular Biology and Gene Therapy, University of Guadalajara, 44100 Guadalajara, Mexico.
authors.forename: Edgar J
authors.initials: EJ
authors.lastname: Mendivil
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. Electronic address: derek.mann@newcastle.ac.uk.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D002251:Carbon Tetrachloride / Q000009:adverse effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006657:Histones / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D006657:Histones; C048460:3-deazaneplanocin; D002251:Carbon Tetrachloride; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000241:Adenosine
keywords: 3-deazaneplanocin A; EZH2; epigenetic; hepatic stellate cells; liver fibrosis