Musashi-1 promotes cancer stem cell properties of glioblastoma cells via upregulation of YTHDF1

Abstract

Background Glioblastoma (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 results In this study, we investigated the expression of five YTH family proteins in different GBM microarray datasets from the Oncomine database, and identified YTHDF1 as the most highly overexpressed member of this family in GBM. By performing the knockdown of YTHDF1 in a GBM cell line, we found that it positively regulates proliferation, chemoresistance and cancer stem cell-like properties. Musashi-1 (MSI1) is a postranscriptional gene expression regulator associated with high oncogenicity in GBM. By knocking down and overexpressing MSI1, we found that it positively regulates YTHDF1 expression. The inhibitory effects imposed on the processes of proliferation and migration by YTHDF1 knockdown were shown to be partially rescued by concomitant overexpression of MSI1. MSI1 and YTHDF1 were shown to be positively correlated in clinical glioma samples, and their concomitant upregulation was associated with decreased survival of glioma patients. We identified the direct regulation of YTHDF1 by MSI1. Conclusions Given the fact that both proteins are master regulators 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 and therapy potential, these two proteins should be considered together.

YTHDF1 promotes the proliferation, migration, and invasion of prostate cancer cells by regulating TRIM44

“…As a reversible epigenetic modification, m6A is associated with the occurrence, metastasis, and drug resistance of tumors (Huang et al 2020). YTHDF1 plays an essential role in a variety of cancers as a core factor of RNA methylation modification (Yarmishyn et al 2020;Zhang et al 2020). However, its specific mechanism in PCa has not been defined.…”

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

“…YTHDF2 has been found to regulate glucose metabolism via the stabilization of the proto-oncogene MYC in glioblastoma stem cells ( Dixit et al, 2020 ). Elevated YTHDF1 was associated with poor prognosis as it is thought to promote the proliferation and migration of glioblastoma cells ( Yarmishyn et al, 2020 ). HNRNPC contributes to glioma progression although the mechanisms underlying this association are not yet known ( Wang L.C.…”

Musashi–1—A Stemness RBP for Cancer Therapy?

“…Prospectively, MSI1–directed post–transcriptional control of gene expression could become even more complex involving RNA modifications, such as m6A (N6–methyladenosine), becoming more critical for cancer development [ 24 ]. In this view, it was previously shown that MSI1 promotes cancer stem cell properties of glioblastoma cells via upregulation of the m6A reader YTHDF1 (YTH N6–methyladenosine RNA–binding protein 1) [ 25 ].…”

“…The functional impact of MSI1 in cancer was studied on the basis of loss– as well as gain–of function studies, including shRNA–, siRNA–, morpholino–directed impairment of MSI1 abundance and its overexpression [ 14 , 19 , 22 , 23 , 25 , 47 , 65 , 69 , 75 ]. Despite technical limitations and flaws of individual studies, there is an overarching agreement in that MSI1 is a potent regulator of various cancer hallmark pathways such as proliferation, apoptosis, anoikis resistance and self–renewal, migration, invasion and EMT (epithelial–mesenchymal transition), as well as tumor growth in vivo.…”

“…CSCs are thought to substantially promote cancer progression and therapy resistance to radiation or chemotherapeutics such as temozolomide [ 44 , 78 , 79 , 80 , 81 , 82 ]. This is associated with neurosphere formation of glioblastoma and medulloblastoma–derived cell lines and tumor growth promoted by MSI1 in vitro and in vivo [ 22 , 25 , 43 ].…”