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Doctoral Thesis
DOI
https://doi.org/10.11606/T.17.2023.tde-08082023-141956
Document
Author
Full name
Graziella Ribeiro de Sousa
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2023
Supervisor
Committee
Tone, Luiz Gonzaga (President)
Brunaldi, Mariângela Ottoboni
Ferraz, Victor Evangelista de Faria
Reis, Rui Manuel Vieira
 
Title in Portuguese
Identificação de potenciais biomarcadores epigenéticos em ependimomas supratentoriais
Keywords in Portuguese
Ependimoma
Ependimoma supratentorial
Histonas desacetilases
Metilação de DNA
ST-ZFTA
Abstract in Portuguese
O ependimoma (EPN) é o terceiro tumor do sistema nervoso central mais comum em crianças. Atualmente é subdivido em dez subgrupos moleculares, sendo os EPNs supratentoriais (ST) (YAP1 e ZFTA) e fossa posterior Grupo A (FPA) os mais prevalentes na infância. O subgrupo ST-ZFTA corresponde a cerca de 70% dos EPNs-ST e tem o pior prognóstico clínico. Modificações epigenéticas contribuem para o desenvolvimento e progressão dos tumores e são promissores alvos terapêuticos. No entanto, há poucas evidências da importância da metilação diferencial e do papel de enzimas reguladoras epigenéticas na tumorigênese de ST-ZFTA. O objetivo deste estudo foi identificar genes diferencialmente metilados com potencial valor prognóstico e entender as vias e processos biológicos envolvidos na progressão tumoral de EPNs ST-ZFTA. Foi explorada a distribuição de CpGs entre ST-ZFTA e ST-YAP1, com ST-ZFTA apresentando perfil hipermetilado em comparação ao ST-YAP1. A expressão gênica de DNA metiltransferases (DNMTs) foi analisada, com DNMT1 e DNMT3A apresentando maior expressão gênica no subgrupo ST-ZFTA em comparação aos subgrupos ST-YAP1 e FPA. Análises in silico identificaram biomarcadores candidatos hipermetilados/hipoexpressos e hipometilados/hiperexpressos entre ST-ZFTA vs. STYAP1. A inibição farmacológica de DNMT usando 5-Aza e Zeb resultou em efeitos antiproliferativos, pró-apoptóticos e parada do ciclo celular (G2/M) na linhagem celular BXD-1425 (ST-ZFTA). Além disso, o RNA-Seq após o tratamento com 5-Aza evidenciou genes candidatos que apresentaram reversão transcricional após a desmetilação. A expressão de dezoito HDACs também foi analisada, sendo que EPNs ST-ZFTA apresentaram maior expressão gênica de HDAC4 em comparação a ST-YAP1 e FPA e baixa expressão de HDAC7 e SIRT2. Nossos resultados identificaram genes candidatos controlados por metilação de DNA com valores prognósticos, além de novos insights sobre HDAC4 em ST-ZFTA. No entanto, mais estudos são necessários para validar os genes candidatos regulados pela metilação do DNA e o envolvimento de HDAC4 isolado ou em combinação com metilação de DNA na carcinogênese de ST-ZFTA.
 
Title in English
Identification of potential epigenetic biomarkers in supratentorial ZFTA ependymomas
Keywords in English
DNA methylation
Ependymoma
Histone deacetylases
ST-ZFTA
Supratentorial ependymoma
Abstract in English
Ependymoma (EPN) is the third most common central nervous system tumor in children. It is currently subdivided in ten molecular subgroups, with supratentorial (ST) EPNs (YAP1 and ZFTA) and posterior fossa Group A (PFA) EPNs being the most prevalent in childhood. The ST-ZFTA subgroup accounts for about 70% of ST-EPNs and has the worst clinical prognosis. Epigenetic changes contribute to the development and progression of tumors and are promising therapeutic targets. However, there is little evidence for the importance of differential methylation and the role of epigenetic regulatory enzymes in ST-ZFTA tumorigenesis. The aim of this study was to identify differentially methylated genes with potential prognostic value and to understand the pathways and biological processes involved in the tumoral progression of ST-ZFTA EPNs. The distribution of CpGs between ST-ZFTA and ST-YAP1 was explored, with ST-ZFTA showing a hypermethylated profile compared to ST-YAP1. The gene expression of DNA methyltransferases (DNMTs) was analyzed, with DNMT1 and DNMT3A showing higher gene expression in the ST-ZFTA subgroup compared to the ST-YAP1 and PFA subgroups. In silico analyses identified candidate biomarkers that were hypermethylated/hypoexpressed and hypomethylated/hyperexpressed between ST-ZFTA vs. ST-YAP1. Pharmacological inhibition of DNMT using 5-Aza and Zeb resulted in anti-proliferative, pro-apoptotic effects, and cell cycle arrest (G2/M) in the BXD-1425 cell line (ST-ZFTA). Additionally, RNA-Seq after treatment with 5-Aza showed candidate genes that exhibited transcriptional reversal after demethylation. The expression of eighteen HDACs was also analyzed, with ST-ZFTA EPNs showing higher gene expression of HDAC4 compared to ST-YAP1 and FPA, and low expression of HDAC7 and SIRT2. Our results identified candidate genes controlled by DNA methylation with prognostic values, as well as new insights into HDAC4 in ST-ZFTA. However, further studies are needed to validate the candidate genes regulated by DNA methylation and the involvement of HDAC4 alone or in combination with DNA methylation in the carcinogenesis of ST-ZFTA.
 
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Release Date
2025-05-22
Publishing Date
2023-08-25
 
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