title: DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression.
abstract: Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression.
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom. Division of Internal Medicine, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Borghesan
authors.affiliation: Bioinformatics Unit, IRCCS "Casa Sollievo della Sofferenza"-Mendel Laboratory, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rappa
authors.affiliation: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Panebianco
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Jude A
authors.initials: JA
authors.lastname: Oben
authors.affiliation: Division of Internal Medicine, Department of Medical Sciences, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mazzoccoli
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Faulkes
authors.affiliation: Department of Gene Technology, Tallinn University of Technology (TTU), IVEX Lab, Tallinn, Estonia.
authors.forename: Illar
authors.initials: I
authors.lastname: Pata
authors.affiliation: Department GF Ingrassia, University of Catania, Catania, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Agodi
authors.affiliation: Department of Cell Biology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Farhad
authors.initials: F
authors.lastname: Rezaee
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Shane
authors.initials: S
authors.lastname: Minogue
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom. Centre for Education and Research on Aging (CERA) and the ANZAC Research Institute, Concord RG Hospital, University of Sydney, Sydney, Australia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Warren
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: Abigail
authors.initials: A
authors.lastname: Peterson
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island.
authors.forename: John M
authors.initials: JM
authors.lastname: Sedivy
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain. Josep Carreras Institute for Leukaemia Research, Campus ICO-HGTP, Campus Can Ruti, Badalona, Spain.
authors.forename: Julien
authors.initials: J
authors.lastname: Douet
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain. Josep Carreras Institute for Leukaemia Research, Campus ICO-HGTP, Campus Can Ruti, Badalona, Spain.
authors.forename: Marcus
authors.initials: M
authors.lastname: Buschbeck
authors.affiliation: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, Palermo, Italy. Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cappello
authors.affiliation: Bioinformatics Unit, IRCCS "Casa Sollievo della Sofferenza"-Mendel Laboratory, Rome, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Mazza
authors.affiliation: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Pazienza
authors.affiliation: Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom. Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy. Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy. School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. m.vinciguerra@ucl.ac.uk.
authors.forename: Manlio
authors.initials: M
authors.lastname: Vinciguerra
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D057890:Epigenomics; D015870:Gene Expression; D056945:Hep G2 Cells; D006657:Histones / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D006657:Histones; D020033:Protein Isoforms; C120756:macroH2A histone; D001616:beta-Galactosidase; D001374:Azacitidine