Laboratory of Cancer Epigenetics and Plasticity, Brown University, Rhode Island Hospital, Providence Rhode Island, United States of America.
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS Genet. 2021 Mar 8;17(3):e1009086. doi: 10.1371/journal.pgen.1009086. eCollection 2021 Mar.
Within the glioblastoma cellular niche, glioma stem cells (GSCs) can give rise to differentiated glioma cells (DGCs) and, when necessary, DGCs can reciprocally give rise to GSCs to maintain the cellular equilibrium necessary for optimal tumor growth. Here, using ribosome profiling, transcriptome and m6A RNA sequencing, we show that GSCs from patients with different subtypes of glioblastoma share a set of transcripts, which exhibit a pattern of m6A loss and increased protein translation during differentiation. The target sequences of a group of miRNAs overlap the canonical RRACH m6A motifs of these transcripts, many of which confer a survival advantage in glioblastoma. Ectopic expression of the RRACH-binding miR-145 induces loss of m6A, formation of FTO/AGO1/ILF3/miR-145 complexes on a clinically relevant tumor suppressor gene (CLIP3) and significant increase in its nascent translation. Inhibition of miR-145 maintains RRACH m6A levels of CLIP3 and inhibits its nascent translation. This study highlights a critical role of miRNAs in assembling complexes for m6A demethylation and induction of protein translation during GSC state transition.
在神经胶质瘤细胞生态位内，神经胶质瘤干细胞 (GSCs) 可以产生分化的神经胶质瘤细胞 (DGCs)，并且在必要时，DGC 可以相互产生 GSCs，以维持最佳肿瘤生长所需的细胞平衡。在这里，我们使用核糖体分析、转录组和 m6A RNA 测序表明，来自不同亚型神经胶质瘤的 GSCs 共享一组转录本，这些转录本在分化过程中表现出 m6A 丢失和翻译增加的模式。一组 miRNA 的靶序列与这些转录本的典型 RRACH m6A 基序重叠，其中许多基序赋予神经胶质瘤生存优势。RRACH 结合的 miR-145 的异位表达诱导 m6A 的丢失、FTO/AGO1/ILF3/miR-145 复合物在临床上相关的肿瘤抑制基因 (CLIP3) 上的形成以及其新生翻译的显著增加。miR-145 的抑制维持 CLIP3 的 RRACH m6A 水平并抑制其新生翻译。这项研究强调了 miRNA 在 GSC 状态转换过程中组装 m6A 去甲基化和诱导蛋白翻译复合物中的关键作用。
