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| Author(s): |
Graziella Ribeiro de Sousa
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2023-05-22 |
| Examining board members: |
Luiz Gonzaga Tone;
Mariângela Ottoboni Brunaldi;
Victor Evangelista de Faria Ferraz;
Rui Manuel Vieira Reis
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| Advisor: | Luiz Gonzaga Tone; Karina Bezerra Salomão Xavier |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 18/23372-4 - Study of the effects of DNA demethylation on genes associated with developmental pathways in pediatric Ependymomas |
| Grantee: | Graziella Ribeiro de Sousa |
| Support Opportunities: | Scholarships in Brazil - Doctorate |