Τίτλος:
Histone Mark Profiling in Pediatric Astrocytomas Reveals Prognostic Significance of H3K9 Trimethylation and Histone Methyltransferase SUV39H1
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. © 2021, The American Society for Experimental NeuroTherapeutics, Inc.
Συγγραφείς:
Klonou, A.
Korkolopoulou, P.
Gargalionis, A.N.
Kanakoglou, D.S.
Katifelis, H.
Gazouli, M.
Chlamydas, S.
Mitsios, A.
Kalamatianos, T.
Stranjalis, G.
Themistocleous, M.S.
Papavassiliou, K.A.
Sgouros, S.
Papavassiliou, A.G.
Piperi, C.
Περιοδικό:
Neurotherapeutics
Εκδότης:
Springer Science and Business Media Deutschland GmbH
Λέξεις-κλειδιά:
2 cyclohexyl n (1 isopropyl 4 piperidinyl) 6 methoxy 7 [3 (1 pyrrolidinyl)propoxy] 4 quinazolinamine; B Raf kinase; chaetocin; complementary DNA; dznep; g34r protein; g34v protein; glyceraldehyde 3 phosphate dehydrogenase; histone; histone H3; histone h3 on lysine 27; histone h3 on lysine 36; histone h3 on lysine 4; histone h3 on lysine 9; histone h3k9; histone H4; histone h4 on lysine 20; histone lysine methyltransferase; histone methyltransferase; histone methyltransferase suv39h1; isocitrate dehydrogenase 1; mithramycin; mithramycin a; mll2 protein; mutant protein; n (1 benzyl 4 piperidinyl) 2 (hexahydro 4 methyl 1h 1,4 diazepin 1 yl) 6,7 dimethoxy 4 quinazolinamine; setd2 protein; setdb1 protein; transcription factor EZH2; unclassified drug; histone lysine methyltransferase; methyltransferase; repressor protein; SUV39H1 protein, human, adolescent; Article; astrocytoma; astrocytoma cell line; brain tissue; cancer prognosis; cancer survival; cell migration; cell proliferation; child; clinical article; comparative study; controlled study; disease association; disease specific survival; epigenetics; female; gene expression; gene expression profiling; genetic association; glioblastoma multiforme cell line; histone code; histone methylation; histopathology; human; human cell; human tissue; male; pediatrics; pilocytic astrocytoma; prognosis; protein fingerprinting; real time polymerase chain reaction; sj gbm2 cell; survival analysis; upregulation; astrocytoma; biosynthesis; brain tumor; cohort analysis; genetics; infant; metabolism; methylation; physiology; preschool child; procedures; tumor cell line, Adolescent; Astrocytoma; Brain Neoplasms; Cell Line, Tumor; Child; Child, Preschool; Cohort Studies; Female; Gene Expression Profiling; Histone Code; Histone-Lysine N-Methyltransferase; Humans; Infant; Male; Methylation; Methyltransferases; Prognosis; Repressor Proteins
DOI:
10.1007/s13311-021-01090-x
