Musashi-1 promotes cancer stem cell properties of glioblastoma cells via upregulation of YTHDF1
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PRIMARY RESEARCH
Cancer Cell International Open Access
Musashi‑1 promotes cancer stem cell properties of glioblastoma cells via upregulation of YTHDF1 Aliaksandr A. Yarmishyn1,2, Yi‑Ping Yang1,2,3, Kai‑Hsi Lu4, Yi‑Chen Chen1, Yueh Chien1, Shih‑Jie Chou1, Ping‑Hsing Tsai1, Hsin‑I. Ma5, Chian‑Shiu Chien1,6, Ming‑Teh Chen2,6,7 and Mong‑Lien Wang1,2,8*
Abstract Background: 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. Methods and results: In 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 gene‑ expression 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 upregula‑ tion was associated with decreased survival ofglioma patients. We identified the direct regulation of YTHDF1 by MSI1. Conclusions: Given 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. Keywords: YTHDF1, Musashi-1, Glioblastoma, Cancer progression Background Gliomas represent the most common type of primary brain tumors originating from glial cells. Glioblastoma (GBM) is the most fatal type of glioma classified by the World Health Organization as a grade IV tumor [1]. GBM is characterized by high level of heterogeneity and pleomorphic morphology, highly infiltrative nature, *Correspondence: [email protected] 1 Division of Basic Research, Department of Medical Research, Taipei Veterans General Hospital, 112 Taipei, Taiwan Full list of author information is available at the end of the article
which allows rapid spread into neighboring brain tissues. The conventional treatment protocol includes maximal safe surgical resection followed by radiotherapy and concomitant chemotherapy with an alkylating agent temozolomide (TMZ), however, the prognosis even for the patients receiving treatment remains dismal with the median survival of only about 14.6 months [2]. Nowadays, it became increasingl
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