Abstract
BackgroundGlioblastoma (GBM) is the most lethal brain tumor characterized by high morbidity and limited treatment options. Tumor malignancy is usually associated with the epigenetic marks, which coordinate gene expression to ascertain relevant phenotypes. One of such marks is m6A modification of RNA, whose functional effects are dependent on the YTH family m6A reader proteins.Methods and resultsIn this study, we investigated the expression of fiveYTH family proteins in different GBM microarray datasets from the Oncominedatabase, and identified YTHDF1 as the most highly overexpressed member of thisfamily in GBM. By performing the knockdown of YTHDF1 in a GBM cell line, wefound that it positively regulates proliferation, chemoresistance and cancerstem cell-like properties. Musashi-1 (MSI1) is a postranscriptional geneexpression regulator associated with high oncogenicity in GBM. By knocking downand overexpressing MSI1, we found that it positively regulates YTHDF1expression. The inhibitory effectsimposed on the processes of proliferation and migration by YTHDF1 knockdownwere shown to be partially rescued by concomitant overexpression of MSI1. MSI1and YTHDF1 were shown to be positively correlated in clinical glioma samples,and their concomitant upregulation was associated with decreased survival ofglioma patients. We identified the direct regulation of YTHDF1 by MSI1.ConclusionsGiven the fact that both proteins are masterregulators of gene expression, and both of them are unfavorable factors in GBM,we suggest that in any future studies aimed to uncover the prognostic value andtherapy potential, these two proteins should be considered together.
Highlights
Glioblastoma (GBM) is the most lethal brain tumor characterized by high morbidity and limited treat‐ ment options
We identified YTHDF1 as the most highly overexpressed m6A reader protein in GBM, and found it to be directly involved in regulating the proliferation of a GBM cell line, as well increasing its resistance to TMZ, and augmenting the Cancer stem cell (CSC) characteristics
MSI1 positively regulates the expression of YTHDF1 through stabilization of mRNA in a GBM cell line Previously, we demonstrated that RNA-binding protein Musashi-1 (MSI1) plays an important tumorigenic role in GBM, controlling such processes as cell migration and drug resistance [25,26,27]
Summary
Glioblastoma (GBM) is the most lethal brain tumor characterized by high morbidity and limited treat‐ ment options. Tumor malignancy is usually associated with the epigenetic marks, which coordinate gene expres‐ sion to ascertain relevant phenotypes. One of such marks is m6A modification of RNA, whose functional effects are dependent on the YTH family m6A reader proteins. GBM is characterized by high degree of cellular, genetic and epigenetic heterogeneity, and the presence of CSCs is believed to be a major determinant for tumor therapy resistance, recurrence and invasive growth [3, 4]. With its high expression in cancers, and its importance in stem cell signaling, MSI1 has been implicated in CSC properties of different tumors, including GBM [9, 10]. In different cellular contexts, MSI can act as an activator of translation [12]
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