title: Emerging role of linker histone variant H1x as a biomarker with prognostic value in astrocytic gliomas. A multivariate analysis including trimethylation of H3K9 and H4K20.
abstract: Although epigenetic alterations play an essential role in gliomagenesis, the relevance of aberrant histone modifications and the respective enzymes has not been clarified. Experimental data implicates histone H3 lysine (K) methyltransferases SETDB1 and SUV39H1 into glioma pathobiology, whereas linker histone variant H1.0 and H4K20me3 reportedly affect prognosis. We investigated the expression of H3K9me3 and its methyltransferases along with H4K20me3 and H1x in 101 astrocytic tumors with regard to clinicopathological characteristics and survival. The effect of SUV39H1 inhibition by chaetocin on the proliferation, colony formation and migration of T98G cells was also examined. SETDB1 and cytoplasmic SUV39H1 levels increased from normal brain through low-grade to high-grade tumors, nuclear SUV39H1 correlating inversely with grade. H3K9me3 immunoreactivity was higher in normal brain showing no association with grade, whereas H1x and H4K20me3 expression was higher in grade 2 than in normal brain or high grades. These expression patterns of H1x, H4K20me3 and H3K9me3 were verified by Western immunoblotting. Chaetocin treatment significantly reduced proliferation, clonogenic potential and migratory ability of T98G cells. H1x was an independent favorable prognosticator in glioblastomas, this effect being validated in an independent set of 66 patients. Diminished nuclear SUV39H1 expression adversely affected survival in univariate analysis. In conclusion, H4K20me3 and H3K9 methyltransferases are differentially implicated in astroglial tumor progression. Deregulation of H1x emerges as a prognostic biomarker.
authors.affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Sepsa
authors.affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.affiliation: Department of Biological Chemistry, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Antonis
authors.initials: A
authors.lastname: Gargalionis
authors.affiliation: Department of Biological Chemistry, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Adamopoulos
authors.affiliation: Department of Biological Chemistry, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Spyropoulou
authors.affiliation: Department of Biological Chemistry, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Dalagiorgou
authors.affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Thymara
authors.affiliation: Department of Neurosurgery, Medical School, National and Kapodistrian University of Athens, Evangelismos Hospital, Athens 106 76, Greece.
authors.forename: Efstathios
authors.initials: E
authors.lastname: Boviatsis
authors.affiliation: Department of Neurosurgery, Medical School, National and Kapodistrian University of Athens, Evangelismos Hospital, Athens 106 76, Greece.
authors.forename: Marios S
authors.initials: MS
authors.lastname: Themistocleous
authors.affiliation: Department of Pathology, Metropolitan Hospital, Athens 185 47, Greece.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Petraki
authors.affiliation: Department of Neurosurgery, Metropolitan Hospital, Athens 185 47, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Vrettakos
authors.affiliation: Department of Pathology, Red Cross Hospital, Athens 115 26, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Samaras
authors.affiliation: Department of Neurosurgery, Red Cross Hospital, Athens 115 26, Greece.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Zisakis
authors.affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.affiliation: Department of Biological Chemistry, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.affiliation: First Department of Pathology, Laikon General Hospital, Athens University Medical School, Athens 115 27, Greece.
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008745:Methylation; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones