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Evaluation of EZH2 expression and activity as factors of cellular susceptibility to Zika Virus infection in embryonic central nervous system tumors

Grant number: 21/04323-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2021
Effective date (End): August 31, 2023
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal researcher:Oswaldo Keith Okamoto
Grantee:Elisa Helena Farias Jandrey
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID

Abstract

Embryonic tumors of the Central Nervous System (CNS), including Medulloblastomas (MEDs) and Atypical Rabatoid Teratoid Tumors (ATRTs), are extremely aggressive tumors that threaten the lives of children, being the main cause of Cancer-related death in the age group 0-4 years. Despite the aggressive therapeutic strategies used to treat these neoplasms (i.e. surgery, radio and chemotherapy), these pathologies have no cure and the available treatments lead to several side effects. In this sense, the Zika Virus (ZIKV) has been explored as a potential agent for the treatment of primary CNS tumors due to its intrinsic neurotropism and its capacity to infect and kill cells of these tumors. In fact, the oncolytic activity of ZIKV has already been demonstrated in glioblastomas and, more recently, a study by our group has shown its oncolytic function in embryonic CNS tumors. Knowing this predisposition for ZIKV infection in CNS cells, it is necessary to better understand the molecular mechanisms involved in the process of infection and death of infected cells in order to develop this technology for the clinic. For this, we performed a pre-analysis of omic data from normal and tumor cells infected by ZIKV and observed a significant enrichment in the expression of genes regulated by the transcriptional factor EZH2. EZH2 is a catalytic subunit of the PRC2 complex, having an important function in the control of gene expression by the trimethylation of Histone H3K27, mainly controlling essential genes for development. EZH2 is overexpressed in embryonic CNS tumors and is directly correlated with the worst prognosis of MEDs. For this reason, EZH2 has been explored as a therapeutic target for both MEDs and ATRTs. To advance the possible involvement of EZH2 in the ZIKV infection process, we submitted three different strains of embryonic CNS tumors (ie USP7-ATRT, USP13-MED and DAOY) to exposure to ZIKV, in the presence or absence of a nonspecific EZH2 inhibitor. (i.e. Metformin). Interestingly, the previous treatment of tumor cells with Metformin was able to delay the cell loss induced by ZIKV in the strains USP7 and USP13. Our preliminary findings suggest that EZH2 activity may be an important factor of susceptibility to the oncolytic effect of ZIKV, a hypothesis that should be further investigated. Thus, the main objective of this work is to evaluate the impact of the expressed levels of EZH2 on the process of cellular infection with ZIKV in CNS tumor cells. (AU)

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