Τίτλος:
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
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2015 Sepsa et al.
Συγγραφείς:
Sepsa, A.
Levidou, G.
Gargalionis, A.
Adamopoulos, C.
Spyropoulou, A.
Dalagiorgou, G.
Thymara, I.
Boviatsis, E.
Themistocleous, M.S.
Petraki, K.
Vrettakos, G.
Samaras, V.
Zisakis, A.
Patsouris, E.
Piperi, C.
Korkolopoulou, P.
Εκδότης:
Public Library of Science
Λέξεις-κλειδιά:
chaetocin; histone H1; histone H1x; histone H3; histone H4; histone lysine methyltransferase; histone lysine methyltransferase inhibitor; temozolomide; unclassified drug; histone; tumor marker, adult; aged; Article; astrocytoma; brain region; brain surgery; cancer cell culture; cancer grading; cancer growth; cancer prognosis; cancer radiotherapy; cancer survival; cell migration; cell proliferation; clinical feature; colony formation; controlled study; correlation analysis; cytoplasm; female; histone methylation; histopathology; human; human cell; human tissue; immunoreactivity; inhibition kinetics; major clinical study; male; multivariate analysis; overall survival; protein expression; univariate analysis; very elderly; Western blotting; brain; cell motion; cohort analysis; glioblastoma; immunohistochemistry; Kaplan Meier method; metabolism; methylation; middle aged; mortality; prognosis; tumor cell line; young adult, Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Brain; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cohort Studies; Female; Glioblastoma; Histones; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Methylation; Middle Aged; Neoplasm Grading; Prognosis; Young Adult
DOI:
10.1371/journal.pone.0115101
