H/ACA snoRNAs and snoRNPs Dysregulation Links rRNA Modification to Glioblastoma Progression

TL;DR

This study shows that certain small RNA molecules are abnormally active in glioblastoma and could be targeted to treat the disease.

Contribution

The study introduces a new method to profile snoRNA expression in glioblastoma and identifies potential therapeutic targets.

Findings

Dysregulation of H/ACA snoRNAs and snoRNPs is linked to glioblastoma progression and poor patient survival.

Knockdown of specific snoRNAs using antisense oligonucleotides significantly reduces GBM cell growth.

Altered snoRNA expression correlates with stemness and differentiation in glioblastoma cells.

Abstract

Small nucleolar RNAs (snoRNAs) are critical players in ribosome biogenesis and have essential roles in rRNA processing and modification (2’O methylation and pseudo-uridylation). snoRNAs define which nucleotides get modified by guiding small nucleolar ribonucleoprotein complexes (snoRNPs) to specific positions in rRNA via base pairing. Altered snoRNA expression has been reported in diverse biological and pathological contexts. In cancer cells, the dysregulation of snoRNAs can alter the rRNA modification landscape, potentially affecting ribosome composition and translation. In aggressive tumors, such as glioblastoma (GBM), snoRNA profiling is crucial for expanding our understanding of ribosome biogenesis and identifying novel biomarkers and therapeutic targets.

We have developed an Ampliseq platform and analysis pipeline to measure the expression of 127 snoRNAs (mostly those containing H/ACA boxes) and Cajal body–specific RNAs (scaRNAs) and conducted a study in a panel of glioma stem cell (GSC), GBM, and normal neuronal lines/tissue.

The results of our Ampliseq analysis identified snoRNAs and scaRNAs (snoRNAs/scaRNAs) that were differentially expressed in GBM and GSC cells compared to normal neuronal cells/tissue, as well as snoRNAs/scaRNAs associated with stemness and differentiation. SnoRNAs with elevated expression in GSC and GBM lines (snoRA38, snoRA51, snoRA71, and snoRA75) have been previously implicated in cancer development. Components of the H/ACA snoRNP complex, which regulate snoRNA processing and rRNA pseudouridylation, were also found to be overexpressed in GBM and showed decreased levels during neuronal differentiation. Notably, high expression of Dyskerin (DKC1)—the pseudouridylation enzyme and a key H/ACA snoRNP component—correlates with poor survival in patients with high-grade gliomas. Finally, we assessed the therapeutic potential of targeting snoRNAs in GBM. Knockdown of two upregulated snoRNAs, snoRA46 and snoRA75, using antisense oligonucleotides significantly impaired GBM cell growth.

snoRNA/scaRNAs profiling revealed distinct alterations in snoRNA expression between glioblastoma and normal neuronal cells. These differences may contribute to the reprogramming of rRNA modification and ribosome composition in cancer cells. Moreover, our findings highlight the potential of antisense oligonucleotide-based targeting of overexpressed snoRNAs in GBM as a promising therapeutic strategy.

Figures