show Abstracthide AbstractGlioblastoma (GBM) ranks among the most lethal of human cancers, containing glioma stem cells (GSCs) that display therapeutic resistance. Here, we report that the lncRNA INHEG is highly expressed in GSCs compared to differentiated glioma cells (DGCs) and promotes GSC self-renewal through control of rRNA 2'-O-methylation. INHEG induces the interaction between a novel SUMO E3 ligase TAF15 and NOP58, a core component of snoRNP that guides rRNA methylation, to regulate NOP58 sumoylation and accelerate the C/D box snoRNP assembly. INHEG activation enhances rRNA 2'-O-methylation, thereby increasing the translation of oncogenic proteins including EGFR and IGF1R in glioma cells. Taken together, this study identifies a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs, supporting a new axis for potential therapeutic targeting of gliomas. Overall design: We report a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs. To interrogate the signaling pathways modulated by methyl transferase FBL, we performed RNA-seq of 3565 and MGG4 cells with FBL knockout compared to non-targeting control. Furthermore, we explored the RNA interactome of NOP58 using ultraviolet cross-linked immunoprecipitation followed by RNA sequencing (uvRIP-seq). We report a lncRNA that connects snoRNP-guided rRNA 2'-O-methylation to upregulated protein translation in GSCs. To investigate the role of rRNA methylation in the tumor hierarchy, we measured the rRNA 2'-O-Me levels in two matched patient-derived GSCs (3565, MGG4) and DGCs with RiboMethSeq. To interrogate the signaling pathways modulated by methyl transferase NOP58, we performed transcriptome sequencing of 3565 and MGG4 cells with NOP58 knockout compared to non-targeting control. Furthermore, we conducted ribosome profiling (Ribo-seq) and RNA-seq to identify the mRNA that lncRNA INHEG regulates.