A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• Small nucleolar RNAs (snoRNAs) regulate RNA modifications, primarily in ribosomal RNA (rRNA).
• Dysregulation of snoRNAs is observed in various cancers, but their precise roles in homeostasis and transformation are not fully understood.
• Oncogenic RAS signaling profoundly impacts cellular processes, yet its earliest effects on snoRNA expression and function remain largely unexplored.

Purpose of the Study:

• To investigate the role of snoRNAs in the early cellular response to oncogenic RAS.
• To elucidate the function of the H/ACA snoRNA SNORA24 in RAS-induced senescence and liver cancer development.
• To determine the impact of SNORA24-guided modifications on ribosome biophysical properties and translation fidelity in hepatocellular carcinoma (HCC).

Main Methods:

• Differential expression analysis of snoRNAs in response to oncogenic RAS G12V.
• In vivo studies using mouse models to assess the cooperative effect of Snora24 loss and RAS G12V in liver cancer.
• Clinical analysis of human HCC tissues to correlate SNORA24 expression with lipid content and patient survival.
• Single-molecule Fluorescence Resonance Energy Transfer (FRET) to analyze ribosome biophysical properties and dynamics.
• Assessment of translational miscoding and stop codon readthrough in HCC cells lacking SNORA24-guided modifications.

Main Results:

• Specific snoRNAs are differentially regulated upon oncogenic RAS G12V expression.
• Loss of SNORA24 cooperates with RAS G12V to promote steatohepatitic HCC development in mice.
• Low SNORA24 expression in human HCC correlates with increased lipid content and poorer patient survival.
• Ribosomes lacking SNORA24-guided pseudouridine modifications exhibit altered aa-tRNA selection and ribosome complex dynamics.
• HCC cells with deficient SNORA24 modifications show increased translational miscoding and stop codon readthrough.

Conclusions:

• SNORA24 plays a critical role in RAS-induced senescence and acts as a tumor suppressor in liver cancer.
• RAS-regulated H/ACA snoRNAs, like SNORA24, influence ribosome biophysical properties, impacting translation fidelity.
• These findings reveal a novel mechanism by which snoRNAs safeguard against oncogenic insults and highlight their potential as therapeutic targets in HCC.