Yarmishyn Aliaksandr A, Yang Yi-Ping, Lu Kai-Hsi, Chen Yi-Chen, Chien Yueh, Chou Shih-Jie, Tsai Ping-Hsing, Ma Hsin-I, Chien Chian-Shiu, Chen Ming-Teh, Wang Mong-Lien
Division of Basic Research, Department of Medical Research, Taipei Veterans General Hospital, 112, Taipei, Taiwan.
School of Medicine, National Yang-Ming University, 112, Taipei, Taiwan.
Cancer Cell Int. 2020 Dec 14;20(1):597. doi: 10.1186/s12935-020-01696-9.
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.
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.
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.
胶质母细胞瘤（GBM）是最致命的脑肿瘤，其特点是发病率高且治疗选择有限。肿瘤恶性通常与表观遗传标记相关，这些标记协调基因表达以确定相关表型。此类标记之一是RNA的m6A修饰，其功能效应取决于YTH家族m6A阅读蛋白。
在本研究中，我们调查了来自Oncomine数据库的不同GBM微阵列数据集中五种YTH家族蛋白的表达，并确定YTHDF1是该家族在GBM中表达最高的成员。通过在GBM细胞系中敲低YTHDF1，我们发现它正向调节增殖、化疗耐药性和癌症干细胞样特性。Musashi-1（MSI1）是一种与GBM高致癌性相关的转录后基因表达调节因子。通过敲低和过表达MSI1，我们发现它正向调节YTHDF1表达。MSI1的过表达可部分挽救YTHDF1敲低对增殖和迁移过程的抑制作用。在临床胶质瘤样本中，MSI1和YTHDF1呈正相关，它们的共同上调与胶质瘤患者生存率降低相关。我们确定了MSI1对YTHDF1的直接调节作用。
鉴于这两种蛋白都是基因表达的主要调节因子，且它们在GBM中都是不利因素，我们建议在任何旨在揭示预后价值和治疗潜力的未来研究中，应将这两种蛋白一起考虑。
